4,4-dihydroxy-2-butenoic acid lactones



United States Patent Olfice Patented Apr. 1, 1969 3,436,3904,4-DIHYDROXY-2-BUTENOIC ACID LACTONES Yvon Lefebvre, Pierrefonds,Quebec, and Jean Marie Ferland, Ville St. Leonard, Quebec, Canada,assignors to American Home Products Corporation, New York, N.Y., acorporation of Delaware No Drawing. Continuation-impart of applicationSer. No. 552,397, May 24, 1966. This application Apr. 10, 1967, Ser. No.629,400

Int. Cl. C07c 173/00; A61k 17/00 US. Cl. 260-23957 25 Claims ABSTRACT OFTHE DISCLOSURE This application is a continuation-in-part of ourearlierfiled US. patent application Ser. No. 552,397, filed May 24, 1966now abandoned.

This invention relates to steroids which possess a 4,4-dihydroxy-Z-butenoic acid lactone joined to the C-l7 position of thesteroid nucleus, to the intermediates used in their preparation, and toa process for preparing the compounds of this invention.

More specifically, this invention relates to novel steroids of generalFormula 'II, in which Sf represents a steroid radical of the estrane orandrostane series and R represents hydrogen or a lower aliphatic acylgroup. These novel steroids are prepared in accordance with ourinvention by a process which utilizes, as starting materials, thecorresponding 17-B3'-furyl]-substituted steroids of general Formula I inwhich St has the same significance as above.

This process may be represented as follows:

Again more specifically, this invention relates to novel steroids of thegeneral Formula II in which the radical 51 represents radicals of thegeneral Formulae III and VI in which R represents hydrogen, a loweralkyl group containing from 1-4 carbon atoms, a cycloalkyl groupcontaining from -6 carbon atoms or an acyl group such as, for examplethe acetyl, propionyl, or butanoyl group; R represents two atoms ofhydrogen, a hydroxyl group and a hydrogen atom, or an oxygen atom; Rrepresents a methyl group or a hydrogen atom; R represents a hydroxylgroup or a lower aliphatic acyloxy group such as, for example, theacetoxy, propionyloxy or butanoyloxy group and a hydrogen atom or anoxygen atom; 'R represents two atoms of hydrogen, a hydroxyl or a loweraliphatic acyloxy group such as, for example, the acetoxy, propionoyloxyor butanoyloxy group and one atom of hydrogen, or an oxygen atom; Rrepresents a hydrogen, or a lower aliphatic acyl group, such as, forexample, the

acetyl, propionyl or butanoyl group; X represents a hydrogen, hydroxylor a lower aliphatic acyloxy group such as, for example, the acetoxy,propionyloxy or butanoyloxy group; and Y represents hydrogen or ahydroxyl group. The dotted lines in ring B of Formula III indicate thattwo double bonds in positions 6,7 and 8,9 may be present.

The novel products of this invention have estrogenic, implantationinhibiting, uterotropic, antigonadotropic, cardiotonic,antiinflammatory, andregenic, anabolic, cholesterol lowering, andmineralocorticoid activities. For example, the novel steroids whichcontain the radical III possess estrogenic, implantation inhibiting,uterotrophic and antigonadatropic activities; those which contain theradical IV possess cardiotonic, mineraloc-orticoid, antiinfiammatory andchloresterol lowering activities; those which contain the radical Vpossess androgenic and anabolic activities; and those which contain theradical VI possess cardiotonic and mineralocorticoid activites. Thecompounds of this invention may be administered orally in the form oftablets or capsules containing 1 to mg. of the active ingredients or byinjection in the form of pharmaceutically acceptable sterile solutionsor suspensions in oily vehicles containing from 1 to 100 mg. of theactive ingredient on a daily basis or as directed by a physician.

When the starting material, or starting materials, of Formula I, asgiven above, contain in their steroid radical portions, elements whichwould render these starting materials subject to attack by the organicperacid at that steroid radical portion, it is then first necessary, inaccordance with conventional principles of organic chemistry, :toprotect the molecule against attack at said steroid radical portion. Forexample, when an isolated double bond is present in the St portion ofthe molecule it is first necessary to protect that isolated double bondagainst attack by the peracid utilizing protective procedures ofconventional type. This is fully understood by organic chemists who areskilled in the chemistry of steroid compounds. Where the St moiety ofthe starting material contains no isolated double bond, or double bonds,or other elements which might render it attackable -by the peracid inits steroid radical portion, then no such pro tective measures areneeded.

The starting material of general Formula I, suitably protected ifnecessary in its St portion is preferably brought into contact with theorganic peracid in the presence of a nucleophilic reagent such as aceticacid or water. Preferably approximately the same amounts of nucleophilicreagent and starting material are employed Among organic peracids whichare capable of being utilized in our process, We have obtained very goodresults with peracids such as peracetic acid, perbenzoic acid,monoperphthalic acid, m-chloroperbenzoic acid, and pnitroperbenzoicacid. The organic peracid utilized may range in amount fromapproximtaely 1.1 molar equivalent to 100 molar equivalents, per mole ofsteroid starting material. Any practical solvent inert to the peracidand nucleophilic reagent may be employed. Aliphatic and cyclic ethers,such as, for example, diethyl ether, dioxan, or tetrahydrofuran; loweraliphatic ketones such as, for example, acetone or methyl ethyl ketone;aromatic hydrocarbons such as, for example benzene, toluene, or xylene;lower aliphatic alcohols, such as, for example, methanol, ethanol,isopropanol, or t-butanol; lower aliphatic acids and their lower alkylesters such as, for example, acetic acid, ethyl acetate, or butylacetate; and halogenated hydrocarbons such as, for example, chloroform,methylene chloride, carbon tetrachloride, or ethylene dichloride, areall useful inert solvents. The time of reaction may extend from 15minutes to 60 hours, with the preferred range being from one half totwenty-four hours. The reaction temperature may be from 10-50 C., withthe preferred range being from 20-30 C. The reaction product is isolatedby washing with water or saturated sodium chloride solution, or byextraction with a water-immiscible solvent, followed by washing withbicarbonate solution, and evaporation. The crude products are purifiedby chromatography or crystallization.

In this manner, there are obtained the novel steroids of Formula II, inwhich R represents hydrogen. Such compounds may be acylated by treatmentwith the appropriate lower aliphatic acid anhydrides or acid halides inthe presence of a basic solvent, to obtain the corresponding acylatedcompounds of Formula II in which R represents a lower aliphtaic acylgroup.

More specifically, we prefer to use as starting materials for thepreparation of the novel steroids of this invention certain17-[3'-furyl] substituted steroids of general Formula I in which theradical St represents radicals of the general Formulae III to VI asdefined above.

The starting materials of the general Formula I, wherein the radical Stis represented by Formula 111 in which R is as defined above and Xrepresents a 17,8-hydroxyl group, are described in US. Pat. No.3,271,392.

The starting materials of the general Formula I wherein the radical Stis represented by Formulae IV or V in which R R and R are as definedabove and X represents a 17fl-hydroxy group, are obtained by reactingthe corresponding 17-keto derivatives VII or VIII, respectively, inwhich R and R 0 0 H30 H30 /\i RI Hi0 i l l o i R:

VII VIII dione or androstane-3,ll,l7-trione (n.b.: An ll-keto grouprequires no protection during the course of this addition reaction).Such temporary protection is advantageously afforded, for example, by anethylenedioxy group, a methyl or ethyl enol ether, or a pyrrolidinylenamine in the case of the derivatives of Formula VII or by a dimethyl,or diethyl acetal group or an ethylenedioxy group in the case of thederivatives of Formula VIII in which R represents oxygen. Theseprotecting groups may be conveniently and specifically removed bysubjecting the resulting products to hydrolysis under mildly acidicconditions, for example with dilute hydrochloric acid in methanol. Alsoduring the course of this reaction it is desirable but not essential toprotect the 3- hydroxy group of compounds of Formula VIII in which R isas defined above and R represents a hydroxyl group and a hydrogen atomin order to avoid the wasteful and useless formation of a complexbetween the hydroxyl and the furyllithium. Such protection is readilyprovided, for example, by a tetrahydropyranyl ether which subsequentlycan be easily and specifically removed by mild acidic conditions, forexample, by dilute hydrochloric acid in methanol. Subsequently,preferential acylation of the 3-hydroxy group, if present, may beaccomplished by treating the just described starting materials with theappropriate lower aliphatic acid anhydrides or acid halides in thepresence of a basic solvent at room temperature. The 11-keto-17a-furylcompounds, as described above, may be reduced to the correspondingllfl-hydroxy-derivatives, preferably when the protective group inpositon 3 is present.

The l7a-[3'-furyl]-substituted starting materials of general Formula Iin which the St radical represents radicals of the Formulae III, IV or Vin which R, R R and R are as defined above and X represents a 17,8-hydroxy group have a threefold use.

First, they may be treated with an organic peracid as described above toyield the novel steroid of this invention of Formula II in which R ishydrogen and the St radical represents a radical of the Formulae III toV in which R R R and R have the same significance as defined above and Xrepresents a l7B-hydroxy group.

Second, these 17a-[3-furyl] substituted steroids of Formula I may beacylated at the tertiary hydroxyl group in position 17 by heating themwith a mixture of the appropriate acid anhydride or acid chloride at C.for 24 hours; under these conditions a 3-hydroxy group, if present, willalso be acylated. The products of this latter treatment are then reactedwith an organic peracid as described above to yield the novel steroidsof this invention of Formula II in which R is hydrogen, and in which theSt radical represents radicals of the Formulae III to V in which R, R Rand R have the same significance as above and X represents a17fi-acyloxy group such as, for example, the acetoxy, propionyloxy orthe butanoyloxy group.

Finally, these l7a-[3'-furyl] substituted steroids may be converted tothe starting materials of general Formula I in which the St radicalrepresents radicals of the Formulae III to V1, in which R R R and R havethe same significance as described above and X represents aUte-hydrogen. This latter conversion is schematically represented byFormulae IX X XI in which Q represents rings A, B and C of the steroidradicals III to V as defined above and is readily accomplished bysubjecting the 17a-[3'-furyl]-substituted steroids, represented byFormula IX, such as, for example, l7a-[3'-furyl]-3-methoxy-l,3,5(10)-estratrien-17-ol, to the dehydrating action of astrong inorganic or organic acid, preferably hydrochloric acid orp-toluenesulfonic acid, in an inert solvent such as, for example,benzene, or by the dehydrating action of phosphorus oxychloride orthionyl chloride in pyridine. The resultant product of general FormulaX, for example, 17 [3' furyl] 3-methoxy-l,3,5(l0),16-

estratetraene may then be hydrogenated using palladium IX XI on calciumcarbonate to afford the l7fl-[3-furyl]-substituted steroid of generalFormula XI, for example, 175- [3-furyl]-3-methoxy-1,3,5(10)-estratriene.However, if the 17a-[3'-furyl]-substituted steroid IX contains a 3-ketone conjugated with a double bond at position 4,5, for example, 17:![3-furyl]-17-hydroxy-4-androstene-3,1ldione, it is preferable to reactsaid steroid with ethylene glycol in the presence of a small amount ofp-toluenesulfonic acid thereby obtaining the 3-ethylenedioxy group whilesimultaneously introducing a double bond at position 16,17 and shiftingthe double bond at position 4,5 to position 5,6. Subsequent preferentialhydrogenation of the double bond at position 16,17 with palladium oncalcium carbonate followed by mild acid treatment to remove theethylenedioxy group affords the 17/3-[3'- furyl]-substituted steroids ofgeneral Formula I in which St represents the steroid radical of FormulaIV and R and R have the same significance as defined above, and Xrepresents a 17a-hydrogen, for example, 17;8-[3-furyl]-4-androstene-3,11-dione. Alternatively, the llfi-hydroxy derivatives ofthe latter compounds are obtained when the above ll-keto derivatives arereduced, preferably while the 3-ketone is protected. Thel7fi-[3'-furyl]-substituted estranes and androstanes of general FormulaI in which the St radical represents the radicals III to V in which R RR and R have the same significance as described above and X represents aNot-hydrogen are then reacted with an organic peracid as described aboveto yield the novel steroids of this invention of Formula II in which Ris hydrogen and the St radical represents a radical of Formulae III to Vin which R R R and R have the same significance as above and Xrepresents a l7u-hydrogen.

Finally the starting materials of general Formula I in which Strepresents a radical of Formula VI may be prepared by the methoddescribed by Minato and Nagasaki in Chemistry and Industry, 1965, p. 899viz., by reduction with diisobutyl aluminium hydride of the appropriatecardenolides of Formula XII 0 E/ H50 I HO I XII

in which Y represents hydrogen or hydroxyl, R represents two atoms ofhydrogen, hydroxy and one atom of hydrogen, or an oxygen atom, to obtainthe corresponding 17,8-[3-furyl]-substituted androstane derivatives ofgeneral Formula I in which St represents a radical of the Formula VI inwhich R represents represents two hydrogen atoms, hydroxyl and one atomof hydrogen, or an oxygen atom; R' represents hydrogen and Y representsa hydrogen or a hydroxy group; during the course of this reduction it isnecessary to provide temporary protection of the 19-aldehyde groups,such as, for example, the aldehyde group of strophanthidin of FormulaXII in which R represents an oxygen atom and Y represents hydroxyl. Suchtemporary protection is advantageously afforded, for example, by theethylenedioxy group which may be easily introduced by reacting thecompound containing a reactive oxo group with ethylene glycol in thepresence of a small amount of p-toluenesulfonic acid, and saidprotective ethylenedioxy group may be readily removed after completionof the reduction by subjecting the ethylenedioxy-substituted compound tohydrolysis with dilute hydrochloric acid in acetone solution asdescribed by Lingner et al. in Arzneimittelforschung, vol. 13, p. 142(1963).

These 17,9-[3'-furyl]-substituted derivatives of general Formula I inwhich St represents a radical of Formula VI in which R represents twohydrogen atoms, hydroxyl and one atom of hydrogen or oxygen atom, Rrepresents hydrogen and Y represents hydrogen or hydroxyl, may then beacylated at position 3 by treating them with the approprate loweraliphatic acid anhydride or acyl chloride in pyridine solution. Should a19-hydroxyl be present in the molecule, it will also be acylated underthese conditions.

The 17B-[3'-furyl]-substituted androstane derivatives of Formula I inwhich St represents a radical of Formula VI in which R represents twoatoms of hydrogen, hydroxyl and one atom of hydrogen, a lower aliphaticacyl group such as, for example, the acetoxy, propionyloxy orbutanoyloxy group and one atom of hydrogen, or an oxygen atom; Rrepresents hydrogen or a lower ali- 'phatic acyl group and Y representshydroxyl or hydrogen, obtained as above, are then treated with anorganic peracid as described above, to yield the desired steroids ofthis invention of Formula II in which R represents hydrogen and Strepresents a radical of Formula VI in which R R and Y are as defined inthis paragraph.

The products of this invention of Formula II in which R representshydrogen and St represents a radical of the Formulae III to VI, may thenbe acylated by treatment with the appropriate lower aliphatic acidanhydride or acyl halide in the presence of pyridine. In this manner thecorresponding products of this invention of Formula II in which Rrepresents a lower aliphatic acyl group such as, for example, theacetyl, propionyl or butanoyl group, is obtained. Should a 3-hydroxy ora 19-hydroxy group or both be present in the molecule, it or they willbe acylated under these conditions.

The following examples will illustrate the scope of this invention.

EXAMPLE 1 A solution of 17a-[3-furyl]-3-methoxy-1,3,5(10)-estratrien-17-ol (728 mg.) described in U.S. Patent No. 3,271,392,pyridine (14.5 ml.), and phosphorus oxychloride (1.45 ml.), is heated ona steam bath for 1 hour. The mixture is poured in ice-water andextracted with ether. The ether solution is washed with dilute sulfuricacid, sodium bicarbonate and water, dried and evaporated to dryness. Theresidue is discolored by treatment on activated charcoal andcrystallized from methylene chloride ether to give 17 [3' furyl] 3methoxy- 1,3,5(10),l6-estratetraene M.P. 162.5164 C.

Similarly dehydration of 17a-[3-furyl]-1,3,5(10)- estratriene-3,17-diol,also described in U.S. Patent No. 3,271,392, yieldsl7-[3'-furyl]-1,3,5(10),16-estratetraen- 3-ol.

By a similar procedure the 3-ethyl, S-propyl, 3-isopropyl, 3-n-butyl,3-sec.-butyl, 3-cyclopentyl and 3- cyclohexyl ethers of17a-[3'-furyl]-1,3,5(10)-estratriene- 3,17-diol, also described in U.S.Patent No. 3,271,392, are dehydrated to yield the corresponding3-alkoxyor 3 cycloalkoxy 17 [3' furyl] 1,3,5,(10),16 estratetraenes,such as, 3 ethoxy 17 [3' furyl] 1,3,5(10), 16 estratetraene, 17 [3'furyl] 3 propoxy 1,3,-

(l0),16 estratetranene, 17 [3 furyl] 3 isopropoxy 1,3,5(),16estratetraene, 3 n butoxy 17- [3' furyl] 1,3,5(10),16 estratetraene, 3sec. butoxy- 17 [3' furyl] 1,3,5(10),16 estratetraene, 3 cyclopentyloxy17 [3 furyl] 1,3,5(10),16 estratetraene, and 3 cyclohexyloxy 17 [3'furyl] 1,3,5(10)16- estratetraene.

Similarly dehydration of the 3 acyloxy 17a [3'- furyl] 1,3,5 (10)estratrien 17 01, also described in U.S. Patent No. 3,271,392, yieldsthe corresponding 3- acyloxy 17 [3 furyl] 1,3,5(10),16 estratetraenes,such as, for example, 3 acetoxy 17 [3 furyl]-1,- 3,5(10),16estratetranen, 17 [3 furyl] 3-propionyloxy 1,3,5 (10),16 estratetraene,3 butanoyloxy 17 [3 furyl] 1,3,5,(10),16 estratetraene.

EXAMPLE 2 A mixture of 17 [3'-furyl]-3-meth0xy-1,3,5(l0),16-estratetraene (5.5 g.), obtained in Example 1, prehydrogenated 5%palladium on calcium carbonate (5.5 g.), and ethyl acetate (559 ml.), ishydrogenated for 2 /2 minutes. The catalyst is filtered and the filtrateis evaporated to dryness. The residue is chromatographed on alumina. Thefractions eluted with mixtures of benzene and hexane are combined andcrystallized from methylene chloride-hexane to give17p-[3-furyl]-3-methoxy-l,3,5 (10)-estratriene M.P. 147l49 C.

Similarly hydrogenation of 17-[3'-furyl]-1,3,5(10),16- estratetraen-3-olyields 17;? [3 furyl]-1,3,5 (10)-estratrien-3-ol.

By a similar procedure the other 3-alkoxy-17-[3-furyl]- 1,3,5 (10),16estratetraenes and 3 cycloalkoxy-17-[3'-furyl]-1,3,5(10),16-estratetraenes, obtained in Example 1, arehydrogenated to give the corresponding 3-alkoxyland3-cycloa1koxy-17fi-[3-furyl]-1,3,5(10)-estratrienes, such as, forexample, 3-ethoxy-17B-[3'-furyl]-1,3,5(10)- estratriene, 17,8 [3furyl1-3-propoxy l,3,5(10)-estratriene, 3 nbutoxy-17fl-[3'-furyl]-1,3,5(l0)-estratriene, 3-sec.-butoxy-17,8-[3furyl] 1,3,5(10) estratriene, 3- cyclopentyloxy17fi-[3-furyl]-1,3,5(10)-estratriene and 3-cyclohexyloxy-178-[3-furyl]-1,3,5(10)-estratriene.

Similarly the hydrogenation of the 3-acyloxy-17-[3'-fury1]-l,3,5(10),16-estratetraenes, described in Example 1, gives thecorresponding 3-acyloxy-17B-[3-furyl]-1,3,5 (10)-estratrienes such as,for example, 3-acetoxy-17 1H3- furyl]-1,3,5 (10)-estratriene, 17 B[3'-furyl] -3-propionyloxy 1,3,5 (10) estratriene and 3butanoyloxy-17B-[3'- furyl]-1,3,5(10)estratriene.

EXAMPLE 3 A mixture of 3-iodofuran (6.6 g.), ether (182 ml.), and a 0.95N ethereal solution of n-butyllithium (38.4 ml.), is stirred at --60 C.for minutes. A solution of 3-ethoxy-3,5-androstadien-17-one (6.5 g.),prepared as described in J. Org. Chem. vol. 29, 601 (1964), in toluene(260 ml.), is added and the mixture is stirred at room temperature for16 hours. Ether and water are added. The organic phase is separated andfurther washed with water to neutrality. After drying and evaporatingthe solvents, 3 ethoxy-17a-[3-furyl]-3,5-androstadien-17-ol is obtained.A solution of this compound (7.7 g.) in 95 ethanol (320 ml.), and water(53 ml.), is stirred for 16 hours at room temperature with 0.1 Nsolution of hydrochloric acid (107 ml.). Water is added and the mixtureextracted with ether. The ether solution is washed with sodiumbicarbonate and water, dried and evaporated to dryness. The residue ischromatographed on alumina. The fractions eluted with benzene-hexane andbenzene are combined and crystallized from 95% ethanol to yield17a-[3'-furyl]-17-hydroxy-4-andr0sten-3-one M.P. 209- 211 C.

By a similar procedure, 3-ethoxy-3,S-androstadiene-l1, 17-dione,3-ethoxy-3,5-estradien-17-one, and 3-ethoxy-3, 5-estradiene-11,17-dione,prepared respectively from 4- androstcne-3,ll,17-trione, 4-estrene 3,17dione and 4- estrene-3,11,17-trione, according to the method described 8in J. Org. Chem. vol. 29, 601 (1964), yield upon treatment with3-furyllithium3-ethoxy-l7a-[3'-furyl]-17-hydroxy-3,5-androstadien-1l-one, 3ethoxy-l7a-[3-furyl]- 3,5-estradien 17 01 and3-ethoxy-l7a-[3-furyl]-17-hydroxy-3,5-estradien-1l-one. The latercompounds in turn give 170:[3'-furyl]17-hydroxy-4-androstene-3,1l-dione,17a-[3-furyl]-17-hydroxy-4-estren 3 one, and 17a-[3'-furyl]-17-hydroxy-4-estrene 3,11 dione upon mild acid hydrolysis.

EXAMPLE 4 Pyrrolidine (42 ml.) is added dropwise to a boiling solutionof 4-androstene-3,17-dione (42 g.), in methanol (1008 ml.). Aftercooling at 0 C. for 1 hour the resulting 3-[1'-pyrrolidinyl] 3,5androstadien-17-one is filtered, thoroughly washed with methanol anddried.

A solution of 3-iodofuran (47.5 g.), in ether (950 ml.), and a 1.60 Nethereal solution of n-butyllithium (134 ml.), is stirred for 30 minutesat 60 C. Then a solution of 3-[1-pyrrolidinyl]-3,5-androstadien-l7-one(47.5 g.), obtained above, in toluene (1900 ml.), is added. The mixtureis stirred for 16 hours at room temperature and the reaction product isisolated as previously indicated in Example 3 to yield17a-[3-furyl]-3-[1-pyrrolidinyl]-3,5- androstadien-17-ol. A solution ofthis latter compound (62 g.), methanol (805 ml.), acetic acid (124 ml.),sodium acetate (186 g.) and water (186 ml.) is refluxed for 4 hours. Themixture is poured in ice-water and is extracted with ether. The ethersolution is washed with water, sodium bicarbonate and water again, driedand evaporated. The residue is chromatographed on alumina. The fractionseluted with benzene and mixtures of benzene-ether are combined andcrystallized from ethanol yielding 17a-[3-furyl]-17 hydroxy-4-androsten-3-one M.P. 207208 C., identical in all respects with the compoundobtained in Example 3.

EXAMPLE 5 Pyrrolidine (4 ml.) is added to a boiling solution of4-estrene-3,17-dione (10 g.), described in J. Org. Chem. 25, 2248(1960), in methanol (40 ml.). After cooling, the precipitate isfiltered, well washed with methanol and dried to yield 3-[l'pyrrolidinyl]-3,5-est-radien-17-one.

A solution of 3-iodofuran (6.74 g.), ether (135 ml.) and a 1.42 Nethereal solution of n-butyllithium is stirred for 30 minutes at -60 C.A solution of 3-[1'-pyrrolidinyl]-3,5-estradien-17-one (6.74 g.),obtained above, in toluene (270 ml.) is added and the reaction mixtureis left at room temperature for 16 hours. The reaction is worked up asin Example 3 to yield 17a-[3-turyl]-[1'-pyrrolidinyl]-3,5-estradien-17-one. The latter compound ishydrolyzed as in Example 4. The residue is chromatographed on alumina.The fractions eluted with benzene and mixtures of benzene and ethylacetate are combined and crystallized from ethyl acetate to give[3-furyl]-17-hydroxy-4-estren-3-one M.P. 158-159 C.

By a similar procedure 3-[1'-pyrrolidinyl]-3,5-estrene- 11,17-dione,prepared as above from 4-estrene-3,11,17- trione, described in J. Am.Chem. Soc. 78, 1512 (1956), yields 17a-[3'-furyl] 17 hydroxy 3[1'-pyrrolidinyl]- 3,5-estradien-11-one, which upon hydrolysis gives17a- [3 '-furyl]-17-hydroxy-4-estren-3,1l-dione.

EXAMPLE 6 Pyrrolidine (60 ml.) is added dropwise to a boiling solutionof 4 -androstene-3,11,17-trione (60 g.), in methanol (1440 ml.). Themixture is cooled in an ice-bath for 1 hour. The resulting solid isfiltered, well washed with methanol and dried yielding3-[1-pyrrolidinyl]-3,5- androstadiene-l1,17-dione.

A solution of iodofuran (66 g.), in ether (1320 ml.), and an etherealsolution (1.59 N) of n-butyllithium (188 ml.), is stirred at 60 C. for30 minutes. A solution of the above enamine (66 g.) in toluene (2640m1.) is added and the reaction is allowed to proceed at room EXAMPLE 7 Amixture of l1a,l7/3-diacetoxy-4-androsten-3-one (29.7 g.), described inJ. Org. Chem. 18, 1166 (1953), benzene (1487 ml.), ethylene glycol(148.7 ml.), and p-toluenesulfonic acid (2.97 g.) is refluxed andstirred for 20 hours in a flask equipped with a continuous waterseparator. After cooling, the solution is washed with sodium bicarbonateand water, dried and evaporated to yield 1la,17fl-diacetoxy-3,3-ethylene-dioxy-S-androstene, purified bycrystallization with methylene chloride-methanol (with a small amount ofpyridine) M.P. 188-189 C.

A mixutre of the above compound (21.5 g.), sodium hydroxide (5.4 g.),methanol (900 ml.), and water (86 ml.) is refluxed for 20 hours. Thesolvent is partially evaporated. Water is added and the precipitate isfiltered washed and dried, yielding3,3-ethylenedioxy-5-androstene-11a,17/3-diol.

By a similar procedure 11a,17fi-diacetoxy-4-estren-3- one described inJ. Am. Chem. Soc. 78, 1512 (1956), yields a mixture ofl1a,17,3-diacetoxy-3,3-ethylenedioxy- S-estrene and1la,17,8-diacetoxy-3,3-ethylenedioxy-5(10)- estrene, which upon alkalinehydrolysis gives a mixture of 3,3-ethylenedioxy-S-estrene-11a,17fi-dioland 3,3-ethylenedioxy-5(10)-estrene-1lu,17;8-diol.

Similarly 17B-hydroxy-4-androsten-3-one and l7B-hydroxy-4-estren-3-oneare treated with ethylene glycol and p-toluene-sulfonic acid in benzeneto yield respectively, 3,3ethylenedioxy-5-androsten-17601, and a mixtureof 3, 3-ethylenedioxy-5-estren-17 8-01 and 3,3-ethylenedioxy-5(10)-estren-17,B-ol.

EXAMPLE 8 Chromium trioxide (17.2 g.) is cautiously added to drypyridine cooled at 20 C. To this complex a solution of3,3-ethylenedioxy-5-androsten-11a,l7B-diol (17.2 g.) obtained in Example7 in pyridine (172 ml.), is added dropwise. The mixture is stirred for32 hours at room temperature. The mixture is filtered on Celite, thefiltrate is diluted with water, and extracted with ether. The ether iswashed wih dilute sulfuric acid, sodium bicarbonate and water, dried andevaporated yielding, 3,3-ethylenedioxy-S-androstene-l1,17-dione,purified by crystalliza- EXAMPLE 9 A solution of 3-iodofuran (12 g.),ether (240 ml.), and a 1.5 N ethereal solution of n-butyllithium isstirred for 30 minutes at -60 C. A solution of3,3-ethylenedioxy-5-androstene-l1,17-dione (13.1 g.), prepared inExample 8, in toluene (480 ml.) is added and the mixture is stirred atroom temperature for 16 hours. The reaction is worked up as in Example3, yielding 3,3-ethylenedioxy-17:-[3-furyl]-l7-hydroxy-5-androsten-1l-one purified by 10crystallization with methylene chloride-methanol (with small quantitiesof pyridine) M.P. 250-253 C.

By a similar procedure a mixture of 3,3-ethylenedioxy-5-estrene-1l,l7-dione, and 3,3 -ethylenedioxy-5(l0 )-estrene-11,17-dioneobtained in Example 8, is transformed into a mixture of 3,3ethylenedioxy-l7u-[3'-furyl]-17- hydroxy-S-estren-ll-one and3,3-ethylenedioxy-17u-[3'- furyl]-17-hydroxy-5(10)-estren-1l-one, whentreated with 3-furyllithium.

Similarly reaction with 3-furyllithium of3,3-ethylenedioxy-S-androsten-l7-one, and a mixture of3,3-ethylenedioxy-5-estren-17-one and3,3-ethylenedioxy-5(10)-estrenl7-one obtained in Example 8, yieldsrespectively 3,3- ethylenedioxy-17a-[3'-furyl] -5-androsten-17-ol, and amixture of 3,3 ethylenedioxy-17a-[3'-furyl]-5-estren-17-ol and3,3-ethylenedioxy-17u- 3 '-furyl]-5(10)-estren-17-ol.

EXAMPLE 10 A solution of 3,3-ethylenedioxy-l7u-[3-furyl]-l7-hydroxy-S-androsten-ll-one (9.9 g.),described in Example 9, in dry tetrahydrofuran (198 ml.), is addeddropwise to a mixture of lithium aluminum hydride (4.95 g.) andtetrahydrofuran (297 ml.). The mixture is refluxed for 4 hours. To thecold mixture ethyl acetate (40 ml.) is added, followed by a saturatedsodium chloride solution (60 ml.). The inorganic salts are filtered andwashed with tetrahydrofuran. The filtrate is evaporated and the residueis dissolved in a mixture of methylene chloride-ether. The organicsolution is washed with a saturated solution of ammonium chloride andwater dried and evaporated yielding 3,3-ethylene-dioxy-17a- [3'-furyl]-5-androstene-l1,8,17- diol, purified by crystallization withmethanol-ether M.P. l97199 C.

By a similar procedure reduction with lithium aluminium hydride of amixture of 3,3-ethylenedioxy-l7a-[3'- furyl]-17-hydroxy-5-estren-1l-one,and 3,3-ethylenedioxy- 17a [3-furyl]-l7-hydroxy-5(10)-estren-1l-oneobtained in Example 9, yields a mixture of 3,3-ethylenedioxy-17u-[3-furyl]-5-estrene-11 3,17-diol and 3,3 -ethylenedioxy- 17a-[3-furyl]-5(10)-estrene-11 3,17-diol.

EXAMPLE 11 A solution of3,3-ethylenedioxy-l7a-[3-furyl]-5-androstene-11,B,17-diol (7.9 g.),obtained in Example 10, ethanol (316 ml.), water (36.4 ml.), and a 1 Nsolution of hydrochloric acid (104 ml.) is stirred at room temperaturefor 4 hours. The reaction mixture is made alkaline by the addition ofsodium bicarbonate, and the solvent is evaporated to dryness. Theresidue is taken up in ether and water. The ether solution is furtherwashed with water, dried and evaporated. The residue is chromatographedon silica gel. The fractions eluted with mixtures of ethylacetate-benzene are combined and crystallized from methanol-ether togive 11B,17B-dihydroxy-17- [3-furyl]-4-androsten-3-one M.P. 198200 C.

By a similar procedure the 3-ketal of a mixture of 3,3- ethylenedioxy17a-[3-furyl]-5-estrene-115,17 diol and 3,3ethylenedioxy-l7a-[3-furyl]-5(10)-estrene 115,17- diol, described inExample 10, is hydrolyzed to yield 11 3, 17,8-dihydroxy-17-[3 '-furyl]-4-estren-3-one.

By a similar hydrolysis procedure 3,3-ethylenedioxy-17a-[3-furyl]-5-androsten-17-01, and a mixture of 3,3-ethylenedioxy-lh-[3'-furyl]-5-extren-l7-ol and3,3-ethylenedioxy-lh-[T-furyl] -5(10)-estren-17 -ol obtained in Example9 are respectively transformed into 17a-[3'-furylJ-l7-hydroxy-4-androsten-3-one and 17a-[3-furyl]-17-hydroxy-4-estren-3-one.

Similarly hydrolysis of the 3,3ethylenedioxy group in 3,3 ethylenedioxy17oz [3 furyl] 17 hydroxy-S- androsten-ll-one and a mixture of3,3-ethylenedioxy-17a- [3'-furyl]-5-estren-ll-one and3,3-ethylenedioxy-l7a-[3- furylJ-l7-hydroxy-5(10)-estren-11 onedescribed in Example 9 yields respectively 17a-[3-furyl]-l7-hydroxy-4-androstene-3,11-dione and 1711- [3'-furyl]-17-hydroxy-4estrene-3,11-dione.

1 1 EXAMPLE 12 By a similar procedure as described in Example 10, 3-ethoxy 17a [3' furyl] 17 hydroxy 3,5 androstadien-ll-one, and3-ethoxy-17u-[3-furyl]17-hydroxy-3,5- estradien-ll-one obtained inExample 3 are reduced by lithium aluminium hydride in tetrahydrofuransolutions to yield respectively3-ethoxy-17a-[3'-furyl]-3,5-androstadiene-11fi,17-diol and3-ethoxy-l7a-[3'-furyl]-3,5-estradiene11fl,l7-diol.

Removal of the protecting group in the latter two compounds, accordingto the method given in Example 3, yields respectively115,17fl-dihydroxy-17 [3' furyl] 4- androsten-3-one and115,17,3-dihydroxy-17-[3'-furyl]=4- estren-3-one.

EXAMPLE 13 By a similar procedure as described in Example 10, reductionwith lithium aluminum hydride of 17a-[3- furyl]-l7-hydroxy-3-[l'pyrrolidinyl] 3,5-estradie-n-11- one, obtained in Example 5, and17ot-[3-furyl]-17-hydroxy-3-[1-pyrrolidinyl]-3,5 androstadien-ll-one,obtained in Example 6, yields respectively l7u-[3-furyl]- 3-[1-pyrrolidinyl]-3,5-estradiene-115,17-diol and 17a-[3- furyl]-3-[l-pyrrolidinyl]-3,5 androstadiene-l118,17-diol.

Removal of the 3-enamine protecting group in the latter two compounds bythe method of Example 4 yields respectively llfi,l7,8-dihydroxyl7-[3-furyl]-4-estren3 one and115,17,8-dihydroxy-l7-[3-furyl]-4-androsten'3- one.

EXAMPLE 14 In a three-neck flask, equipped with a stirrer and a waterseparator, a solution of 17a-[3-furyl]-17-hydroxy- 4-androsten-3-one (25g.), described in Example 3, benzene (1250 ml.), ethylene glycol 125ml.), and ptoluenesulfonic acid (2.5 g.) is refluxed and stirred for 20hours. The cold solution is washed with bicarbonate and water, dried andevaporated, yielding 3,3-ethylenedioxy-17-[3-fiuryl]5,16-androstadiene,purified by crystallization from methylene chloride-methanol, containinga small quantity of pyridine, M.P. 228231 C.

Similarly ketalization of 17a-[3'-furyl]-17-hydroxy-4- estren-3-one,obtained in Example 5, yields a mixture of3,3-ethylenedioxy-17-[3'-furyl]-5,16-estradiene and 3,3-ethylenedioxyl7- 3 -furyl] ,16-estradiene.

EXAMPLE 15 A mixture of 17a-[3'-furyl]-17-hydroxy-4-androstene-3,11xlione (1 g.), obtained in Example 6, benzene (50 ml.), ethyleneglycol (5 ml.), and p-toluenesultonic acid (100 mg), is refluxed andstirred for hours in a flask equipped with a continuous water separator.The reaction is worked up as in Example 14, yielding 3,3-ethylenedioxya17-[3-furyl] 5,16 androstadien-ll-one, purified bycrystallization with methylene chloridemethanol (with pyridine) M.-P.205207 C.

Similarly ketalization of 17u-[3-furyl]-17-hydroxy-4-estrene-3,11xlione, obtained in Example 5 yields a mixture of3,3-ethylenedioxy-17-[3'-furyl]-5,16-estradien-11- one and3,3-ethylenedioxy-17-[3-furyl]-5(10),16-estradien-ll-one.

EXAMPLE 16 A mixture of3,3-ethylenedioxy-17-[3-furyl]-5,l6-androstadien-ll-one (500 mg.),obtained in Example 15, ethyl acetate (23.5 ml.) and prehydrogenated 5%pallidium on calcium carbonate (125 mg.) is hydrogenated at roomtemperature and at normal pressure for 5 minutes. The catalyst isfiltered and the filtrate is evaporated to dryness yielding3,3-ethylenedioxy-l7;8-[3-furyl]-5-androsten-l l-one, purified bycrystallization from acetonehexane M.P. l76178 C.

By a similar procedure hydrogenation of3,3-ethylenedioxy-17-[3-furyl]-5,l6-androstadiene, obtained in Example14, the mixture of 3,3-ethylenediox'y-17-[3-furyl]- 5,16-estradiene and3,3-ethylenedioxy 17-[3-turyl]-5 (10},16-estradiene, obtained in Example14, and the mixture of3,3-ethylenedioxy-17-[3'-furyl]-5,16-estradien-11- one, and3,3-ethylenedioxy-17-[3'-furyl]-5(l 0),16-estradien-ll-one obtained inExample 15, yields respectively3,3-ethylenedioxy-17/3-[3'-furyl]-5-androstene M.P. 186- 188 C., amixture of 3,3-ethylenedioxy-17fl-[3-furyl]- S-estrene and3,3-ethylenedioxy-17p-[3'-furyl]-5(10)- estrene, and a mixture of3,3-ethylenedioxy-17fl-[3'- furyl]-5-estren-ll-one and 3,3-ethylenedioxyl7;3-[3- furyl] -5 (l0)-estren-l1-one.

EXAMPLE 17 A solution of3,3-ethylenedioxy-1718-[3'-furyl]-5-androsten-ll-one (4.8 g.), obtainedin Example 1 6, in dry tetrahydrofuran (96 ml.), is added dropwise to astirred mixture of lithium aluminum hydride (2.4 g.) in tetrahydrof'uran(144 ml.). The mixture is refluxed for 4 hours. The reaction product isisolated as indicated in Example 10. Crystallization of the crudeproduct from acetonemethanol yields3,3-ethylenedioxy-l7fi-[3-furyl]-5-androsten-1lfl-ol, M.P. 185l87 C.

Similarly reduction with lithium aluminium hydride of the mixture of3,3-ethylenedioxy-17,8-[3-furyl]-5-estrenll-one and 3,3-ethylenedioxy17fl-[3'-furyl]-5 (10)- estren-ll-one, obtained in Example 16, yields amixture of 3,3-ethylenedioxy-17B-[3'-furyl]-5-estren-l1fiol and 3, 3-ethylenedioxy- 17 5- 3 -furyl] -5 10) -estren-1 113-01.

EXAMPLE 18 A mixture of3,3-ethylenedioxy-l7fi-[3-furyl]-5-androsten-llB-ol (2.1 g.), obtainedin Example 17, acetone (88 ml.), and p-toluenesulfonic acid (210 mg.),is refluxed for 1 hour. Water is added and the mixture is extracted withether. The ether is Washed with sodium bicarbonate and water, dried andevaporated, leaving 175- [3-furyl]-11,8-hydroxy-4 androsten-3-one,purified by crystallization from 2-methoxyethano1 and then acetone M.P.207209 C.

Similarly hydrolysis of the 3,3-ethylenedioxy group in the mixture of3,3ethylenedioxy-Ufl-[3'-furyl]-5-estren- -01, and 3,3-ethylenedioxy17fi[3-furyl]-5 (10)- estren-lOfi-ol described in Example 17 yieldsl7fi-[3- furyl] -1 l fl-hydroxy-4-estren-3-one.

EXAMPLE 19 A mixture of 3,3-ethylenedioxy-17;8-[3-furyl]-5-androstene(18.8 g.), obtained in Example 16, acetone (780 ml.), andp-toluenesulfonic acid (1.88 g.) is refluxed for 1 hour. The reaction isworked up as in Example 18, yielding 17,8-[3-furyl]-4-androsten-3-one,purified by crystallization from methanol M.P. 187-188".

Similarly hydrolysis of the 3,3-ethylenedioxy group in the mixture of3,3-ethylenedioxy-17B-[3-furyl]-5-estrene and3,3-ethylenedioxy-17/8-[3-furyl] -5 (10)-estrene described in Example16, yields 17 8-[3-furyl]-4-estren-3- one.

EXAMPLE 20 A mixture of3,3-ethylenedioxy-17B-[3-furyl]-5-androsten-ll-one (6.25 g.), describedin Example 16, acetone (250 ml.), and p-toluenesulfonic acid (637 mg.),is refluxed for 1 hour. The solution is diluted with water and ether.The ether layer is separated, washed with sodium bicarbonate and water,dried and evaporated yielding 17 8-[3furyl]-4-androstene-3,1l-dione,recrystallized from acetone-hexane M.P. 189190 C.

By a similar procedure hydrolysis of the ketal group in the mixture3,3-ethylenedioxy-l7fi-[3-fury1]-5-estren-l1- one and3,3-ethylenedioxy-17fi-[3fury1]-5(10)-estren-11- one, obtained inExample 16, yields 17;? [3 furyl] 4- estrene-3,1 l-dione.

EXAMPLE 21 A mixture of l7a-[3-furyl]-l7-hydroxy-4-androsten-3- one (1g.), obtained in Example 3, methylene chloride (15 ml.), ether (15 ml.),and a 25% hydrochloric acid solution (8 ml.), is stirred at roomtemperature for 18 hours. The water phase is separated and the organicsolution is Washed with sodium bicarbonate and water, dried andevaporated. The residue is crystallized from methanol to yield 17 [3furyl] 4,16 androstadien 3-one M.P. 124126 C.

By a similar procedure l7w-[3'-furyl]-17-hydroxy-4 estrene-3-one, and17a-[3-furyl]-l7-hydroxy-4-estrene- 3,1l-dione, obtained in Example 5,and l7a-[3-furyl]-l7- hydroxy-4-androstene-3,1l-dione, obtained inExample 6 are respectively transformed by acid dehydration to 17- [3'furyl] 4,16 estradien 3 -one, 17-[3'-furyl]-4,l6- estradiene 3,11 dioneand 17-[3-furyl]-4,16-androstadiene-3,11-dione.

EXAMPLE 22 A mixture of 17 [3 furyl] 4,16-androstadien-3-one (7.76 g.),obtained in Example 21, ethyl acetate (360 ml.), and prehydrogenated 5%palladium on calcium carbonate (1.95 g.) is hydrogenated for 5 minutes.The catalyst is filtered and the filtrate evaporated to dryness,yielding 17B [3 furyl] 4-androsten-3-one, purified by crystallizationfrom methanol M.P. 186188 C.

Similarly hydrogenation of 17 [3 furyl]-4,16-estradien-3-one, 17-[3-furyl]-4,16-estradiene-3,ll-dione and 17-[3-furyl]-4,l6-androstadiene-3,ll-dione, obtained in Example 21, yieldsrespectively 17/8-[3-furyl]-4-estren-3- one, 17 8 [3 furyl]4-estrene-3,11-dione and 17 3-[3- furyl] -4-androstene-3 ,1 l-dione.

EXAMPLE 23 A solution of 5oc-andrOStane3,l7-diOne (1 g.), oxalic acid(500 mg), and methanol (15 ml.), is left at room temperature for 90minutes. After cooling the solution to C. the acid is neutralized by theaddition of a cold solution of sodium bicarbonate. The mixture isextracted with ether. The ether is washed with water, dried andevaporated yielding 3,3-dimethoxy-a-androstan-l7-one, purified bycrystallization with hexane (containing a few drops of pyridine) M.P.122125 C.

By a similar procedure 5B-androstane-3,17-dione, described in J. Org.Chem., 25, 1399 (1960), 5a-androstane, 3,11,l7-trione, described inHelv. Chem. Acta, 36, 652 (1953), and 55-androstane-3,11,17-trione,described in Helv. Chem. Acta, 36, 1266 (1953), are transformed in thecorresponding 3,3 dimethoxy Sfl-androstan-l7-one, 3,3 dimethoxy5a-androstane-11,17-dione, and 3,3-dimethoxy-SB-androstane-l 1,17-dione.

A solution of 3-iodofuran (21.4 g.), ether (35 ml.), and a 1.1 Nethereal solution of n-butyllithium (88.9 ml.), is stirred at '60 C. for30 minutes. A solution of 3,3-dimethoxy-5tx-androstan-17-one (21.3 g.),described above, in toluene (500 ml.), is added and the mixture isstirred at room temperature for 16 hours. The reaction is worked up asin Example 3, to give 3,3-dimethoxy-l7a- [3'-furyl]-5a-androstan-17-o1.A solution of the latter compound and oxalic acid g.) in acetone (500ml.), and water (50 ml.), is stirred for 3 hours at room temperature.Addition of water gives 17a-[3-furyl]-17-hydroxy-5a-androstan-3-one M.P.236238 C., crystallized from methylene chloride-hexane.

Similarly, 3,3 dimethoxy-Sfl-androstan-17-one,3,3-dimethoxy-5a-androstane-l1,l7-dione and 3,3-dimethoxy-Sfl-androstane-l1,17-dione, described above, are treated with3-fury1lithium to give 3,3-dimethoxy-l7u-[3-furyl]- 5B androstan-17-ol,3,3-dimethoxy-17ot-[3'-furyl]-l7-hydroxy 5a-androstan-11-one, and3,3-dimethoxy-l7u-[3- furyl]-17-hydroxy-5B-androstan-1l-one,respectively.

Hydrolysis of the dimethoxy group in the above compounds yieldsrespectively, 17a-[3'-furyl]-17-hydroxy-5B- androstan 3 -one,17a-[3'-furyl]-l7-hydroxy-5 x-androstane 3,11 dione, and17a-[3'-furyl]-17-hydroxy-5;3- androstan-3,1l-dione.

EXAMPLE 24 Treatment of 3,3-ethylenediQXy-Sa-and-rostau-17-one,

14 described in Bull. Soc. Chim. Fr., p. 68 (1965), with 3- furyllithiumas in Example 3, yields 3,3-ethylenedioxy- 17w[3'-furyl]=5a-androstanl7-ol, which upon hydrolysis as described in Example 11, is transformedinto 1711- [3'-fury1]-17-hydroxy-5a-androstan-ii-one.

Similarly 3,3-ethylenedioxy-5/8-androstan- 17-one, prepared from'17,8-hydroxy-5B-androstan-3-one, according to the method described inBull. Soc. Chim. Fr., p. 68 (1965), yields3,3-ethylenedioxy-17ot[3-furyl]-5;9-androstan-17-0l, which upon mildacid hydrolysis gives 17a- [3 -furyl] -17-hydroxy-Sfl-androstan-S -oneIn a similar manner 3,3-ethylenedioxy-5,3-androstane- 11,17-dione,prepared according to the method of Examample 8 from11a,17,3-dihydroxy-5;8androstan-3-one, described in US. Patent2,877,162, yields 3,3-ethylenedi-oxy 17 a- [3'-furyl]17-hydroxy-53-androstan-ll-one, transformed by acid hydrolysis to17a-[3'-furyl]-17-hydroxy-5B-androstane-3, 1 l-dione.

EXAMPLE 25 Reduction with lithium aluminum hydride as described inExample 10, of 3,3-dimethoxy-17u-[3'-furyl]-l7-hydroxy-5a-androstan-11-one, and 3,3-dimethoxy-17a-[3'-furyl]-17-hydroxy-5B-androstan-1l-one, obtained in Example 23, yieldsrespectively 3,3-dimethoxy-17a-[3'-furyl] Sa-androstans-115,17-diol, and3,3-dimethoxy417a-[3'- furyl]-5;3-androstane-1-1/i,'17-diol. Hydrolysiof the protecting 3,3-dimethoxy group as described in Example 23, gives11 8,17,3-dihydroxy-17-[3'-furyl]-5a-androstan- 3-one, and 11 3,173-dihydroxy 17-[3furyl]-5fi-androstan- 3-one.

EXAMPLE 26 A solution of 3-iodofuran (26 g.), ether (500 ml.), and a 1.3N etheral solution of n-butyllithium (92.6 ml.) is stirred at 60 C. for30 minutes. A solution of 38- tetrahydropyranyloxy-Sa-androstrln-17-one(26 g.), described in J. Am. Chem. Soc. 83, 1478 (1961), in toluene (700ml.) is added. After stirring for 16 hours at room temperature, thereaction is worked as in Example 3, yielding 17a[3-furyl]-3fi-tetrahydropyranyloxy-Stz-androstan-17-ol.

A solution of the latter product (30.5 g.) p-toluenesulfonic acid (300mg), in methanol (300 ml.) is stirred for 1 hour at room temperature.Addition of water yields 1711-[3-furyl]-5a-androstanef3fi,17-diol,purified by crystallization with ethyl acetate-hexane M.P. 206208 C.

By a similar method 3p-tetrahydropyranyloxy-Sfl-andr-ostan-17-oneprepared by the method described in I. Am. Chem. Soc. 83, 1478 (1961) istreated with 3-furyllithium to give17a-[3'-furyl]-3fl-tetrahydropyranyloxy- 5fi-androstan-17-ol. Hydrolysisof the protecting group in the latter compound gives17a-[3'-fury1]-5,3-androstane-3;3,17-diol.

EXAMPLE '27 A solution of 17a-[3'-furyl]-5a-androstane-'3,6,17-diol 13.0g.), described in Example 26, pyridine ml.) and acetic anhydride (65ml.), is left at room temperature for 16 hours. The reaction mixture ispoured in ice- Water and is extracted with ether. The ether solution isWashed with dilute sulfuric acid, sodium bicarbonate and water, driedand evaporated. The crude product is crystallized from methylenechloride-hexane to give Bil-acetoxy-17ot[3'-furyl]-5a androstan-l7ol,M.P. 133-134" C.

Similarly acylation with acylating agents other than acetic anhydrideyields the corresponding 3/9-acyloxy-17w [3'-furyl]-5a-androstan-17-ol,such as, for example, [3'-furyl] 3/3-propionyloxy-5a-androstan-l7-01,and 3fibutanoyloxy-17a-['3'-furyl] 5a-androstam17-ol.

By a similar procedure acylation of l7a-[3'-furyl]-'5,3-androstane-3fi-17-diol, obtained in Example 26, yields the corresponding3-acyloxy derivatives such as, for example, the 3fi-acetoxy-,3fl-propionyloxyor 3 B-butanoyloxy- 17a-[3-furyl]-5,fi-androstan-17-ols.

1 EXAMPLE 2s A mixture of 17a-[3'-furyl]-17-hydroxy-5a-androstan- 3-one(540 mg), obtained in Example 23, ether (150 ml.), and a 25% solution ofhydrochloric acid (50 ml.), is stirred for 30 minutes. The reaction isworked up as in Example 21, yielding 17-[3'-furyl]-5a-androst- 16-en-3-one, purified by crystallization from methylene chloride-ether M.P.195196 C.

Similarly dehydration of 17a-[3-furyl]-17-hydroxy-5;8- androstan 3 one,17a-[3-furyl]-l7-hydroxy-5u-androstane 3,11-dione, and 170:[3'-furyl]17-hydroxy-5fl-androstane-3,11-dione obtained in Example 23yields respectively 17-[3-furyl]-5;8-androst-16-en-3-one, 17-[3-furyl]-5a-androst-16-ene-3,'11-dione,'17-['3-furyl]-5B-androst-16-ene-3,11-dione.

EXAMPLE 29 Dehydration, according to the precedure described in Example28, of 17a [3 furyl]-5a-androstane-3}3,17-diol and17a-[3'-furyl]*5fl-androstane-3/8,17-diol, described in Example 26,yields respectively i17-[3'-furyl]-5a-androstl6-en-3B-ol, and17-[3-furyl]-5,8 androst-1'6-en-3/8-ol.

By a similar procedure dehydration of the 3fi-acyloxy-17w[3-furyl]-5a-androstan-17-ols, and 3fl-acyloxy-17ot-[3-furyl]-5fl-androstan-17-ols described in Example 27, yields thecorresponding 3,3-acyloxy-l7-[3'-furyl]=5a-androst-l6-enes and3fl-acyloxy-17-[3-furyl]=5fi-androst-16- enes, such as, for example, the35-acetoxy-, 3p-propionyloxyor3fl-butanoyloxy-17-[3'-furyl]-5a-androst-16-enes, and the 3p-acetoxy-,3fi-propionyloxyor 3/S-butanoyloxy- 17- [3-furyl] -5/3-androst-1 6-enes.

EXAMPLE 30 Hydrogenation, according to the procedure given in Example 16of 17-[3-furyl]-5u-androst-16-en-3-oue, 17-[3-furyl]-5y8-androst-l6-en-3-one, 17 [3-furyl]Soc-androst-16-ene-3,11-dione, and 17- [3'-furyl] -5,9-androst-16-ene3,11-dione, described in Example 28, yields respectivelyl7}8-[3'-furyl]-5a-androstan-3-one M.P. l89l91 C.,l7B-[3-furyl]-5,B-androstan-3-one, 173-[3-furyl]-5aandrostane-3,11-dione, and 17 8-[3'-furyl]-5 8-androstane-3,11-dioue.

Similarly hydrogenation of 17-[3-furyl]-androst-16- en-Bfi-ol, and17-[3'-furyl]-5;8-androst-16-en-3;8-ol, obtained in Example 29, yieldsrespectively 17fl-[3'-furyl]- 5ot-androstan-3p-ol, and17B-[3-furyl]-5,8-androstan-3;8- 01.

By a similar procedure the 3p-acyloxy-l7-[3-furyl] -50tandrost-16-enes,and 3;3-acyloxy-l7-[3-furyl]-5 8-androst- 16-enes, obtained in Example29, are hydrogenated to give the corresponding3p-acyloxy-17/8-[3'-furyl]-5a-androstanes, and3fi-acyloxy-l7i3-[3'-furyl]-5fl-androstanes, such as, for example, the3B-acetoxy-, 3fl-propionyloxy- -or3fi-butanoyloxy-l7fi-[3-furyl]-5u-androstanes, and the 3fi-acetoxy-,3/3-propionyloxyor 3p-butanoyloxy-17B-[3- furyl]-5p-androstanes.

EXAMPLE 31 By a similar procedure as described in US. Patent No.3,271,392, acetylation with acetic anhydride in pyridine solution at 100C. for 24 hours, of 17a-[3'-furyl]-17- hydroxy-4-androsten-3-one,obtained in Example 3, 17a- [3-furyl]-17-hydroxy-4-estren-3-one, and17a-[3-furyl]- l7-hydroxy-4-estrene-3,1l-dione, obtained in Example 5,17oz [3'-furyl]-17-hydroxy-4-androstene-3,1l-dione, obtained in Example6,

17:1- [3 -furyl] -17-hydroxy-5 u-androstan-S-Qne,

17a- [3 -furyl] l7-hydroxy-5/3-audrostan-3-one,

17a- 3 '-furyl] -l 7-hydroxy-5ot-androstane-3, l l-dione, and 17w [3-furyl] -17-hydroxy-518-audrostane-3,l l-dione,

described in Example 23, yields respectively 17 ,8-acetoxy-l7-[3'-furyl]-4-androsten-3-one, 17p-acetoxy-17-[3'-furyl] -4-estren-3-one,

1 6 17,8-acetoxy-l7-[3'-furyl]-4-estrene-3,l1-dione,17,8-acetoxy-17-[3-furyl]-4-androsteue-3,1l-dione,17fi-acetoxy-17-[3-furyl] -5a-androstan-3-one, 17/3-acetoxy-17-[3-furyl]-5 8-androstan-3-one, l78-acetoxy-17-[3'-furyl]-5a-androstane-3,1l-dione, andl7/3-acetoxy-l7-[3-furyl] -5B-androstane-3,l l-dione.

Similarly acetylation of 17a-[3-furyl]-5u-androstane- 35,17-dio1 and17a-[3'-furyl]-5fl-audrostane-3;8,17-diol, described in Example 26,yields respectively 3fl,l7';8-diacetoxy-17-[3-furyl]-5a-androstane, and33,17-diacetoxyl7- 3 '-furyl] -5fi-androstane.

EXAMPLE 32 A 25.5% solution of diisobutyl aluminum hydride in drytetrahydrofuran (72 ml.) is added dropwise to a stirred solution ofdigitoxigenin (15.0 g.) in tetrahydrofuran (200 ml.) at a temperaturebetween -20 C. and 25 C. in an atmosphere of nitrogen. The reaction iscontinued for 20 minutes at the same temperature. A 10% aqueous sulfuricacid solution (50 ml.) is added and the mixture is poured into an aqeoussolution of sodim bicarbonate. The mixture is filtered through Celiteand extracted with ether. The ether is washed with water, dried andevaporated to dryness leaving crude 17,6-[3'-furyl]-5p-androstane-3fi,14B-dio1, purified by crystallization frommethylene chloride-ether M.P. 201-203" C.

Similarly, periplogenin and strophanthidol yield, upon reduction withdiisobutyl aluminum hydride as above,17,8-[3-furyl]-androstane-3,8,5,8,14fi-triol and 175 [3'-furyl]-androstane-3;3,55,14,8,19-tetrol.

EXAMPLE 33 In the same manner as described in Example 32, theethyleuedioxy derivative of strophanthidin was reduced to19-ethylenedioxy-17p-[3-furyl]-5p-androstane 318,518, 14B-triol. Thelater compound upon hydrolysis with 0.1 N hydrochloric acid in acetonesolution is transformed intol7;3-[3'-furyl]-3;8,5}9,1418-trihydroxyandrostan-l9-al.

EXAMPLE 34 A solution of 17,8-[3'-furyl]-5 8-androstan-3fl,14,9-diol (10g.) obtained as described in Example 32, pyridine (50 ml.) and aceticanhydride (25 ml.) is allowed to stand at room temperature overnight.Methanol (25 ml.) is added and the solution is poured into ice-water andextracted with ether. The ether is washed with dilute sulfuric acid,sodium bicarbonate and water. After drying and evaporating the solvent,the crude acetate is crystallized from aqueous methanol to yield3B-acetoxy-17B- [3-furyl]-5,8-audrostan-l4,8-ol, M.P. 157 C.

Similarly, acetylation of 17fi-[3'-furyl]-androstane-3B, 55,14fi-trioland 17p-[3'-furyl]-3B,5/3,14fl-trihydroxyandrostan-19-al yields thecorresponding 3 3-acetoxy-175-[3'- -furyl]-androstane-5fl,l4/8-diol and3 8-acetoxy-5p,14;8-dihydroxy-17B-[3'-furyl]-androstan-19-al. By asimilar procedure acetylation of l7,8-[3'-furyl]-androstane 35,55,145,19-tetrol yields 3B,l9-diacetoxy-l7fi-[3'-furyl]androstane-5fi,14p-diol.

EXAMPLE 35 By a similar procedure as described in Example 34, acylationwith the appropriate lower aliphatic acid anhydrides or acyl chloridessuch as, for example, propionic anhydride or butyric anhydride, inpyridine of 17/3-[3'- furyl] 5 3-androstane-3fl,14 8-dio1,I7B-[3-furyl]-androstane-3;8,5;3,l4fl-triol andl7fl-[3'-furyl]-3;3,5}3,l4fi-trihydroxyandrostan-19-al yields thecorresponding 3-acylates, 3-propionyloxy or3B-butyryloxy-17fl-[3'-furyl]-'5fi-androstan-l4/8-ol, 3B-propionyloxy or3,3-butylryloxy-17B-[3'- furyl]-androstane-5/3,l45-diol, 3B-propionyloxyor Sfl-butyryloxy-l7/3 [3'-furyl] Sfl,l4fl-dihydroxyandrostan-19- a1,respectively. In the same manner, acylation as above of17fl-[3-furyl]-androstan-3p,5;8,145,19-tetrol yields the corresponding3fl,l9'-diacylates, 3fi,19-dipropionyloxy or 173,3,19-diblltY1IYlOXY-17oz [3'-furyl] androstane-fl,l4fldiol,respectively.

EXAMPLE 36 A mixture of17a-[3-furyl]-3-methoxy-1,3,5(10)-estratrien-l7-ol (17 g.), described inU.S. Patent No. 3,271,- 392, chloroform (850 ml.), sodium acetate (17g.), acetic acid (17 ml.) and m-chloroperbenzoic acid (85%) (23.65 g.)is stirred at room temperature for 1 hour. Ether is added. The organicsolution is washed with sodium bicarbonate and water, dried andevaporated. The residue is chromatographed on silica gel. The fractionseluted with 2% benzene-methanol are combined and crystallized withacetone-hexane to give 4,4-dihydroxy-3-[17fihydroxy 3''methoxy-1',3',5(10)-estratrien-l7'-yl]-2- butenoic acid lactone, M.P.214216 C.

EXAMPLE 37 A mixture of17a-[3'-furyl]-3-methoxy-l,3,5(l0)-estratrien-l7-ol (6.0 g.), chloroform(67.5 ml.), peracetic acid (27 ml. of a 40% solution), and sodiumacetate (2.7 g.), is stirred for 90 minutes at room temperature. Themixture is diluted with ether and the organic solution is washed withsodium bicarbonate and Water. The solvents are dried and evaporated todryness, yielding (4,4-dihydroxy-3-[l7'fi-hydroxy 3'methoxy-1',3,5'(l0')-estratrien-17'-yl] -2-butenoic acid lactone,identical to the product obtained in Example 3 6.

EXAMPLE 3 8 By a similar procedure as described in Example 36 or 37,'17a-[3'-furyl]-l,3,5(l 0)-estratriene-3,17-diol and the other 3-alkoxyor 3'cycloalkoxy derivatives described in U.S. Patent No. 3,271,392, arerespectively transformed into 4,4-dihydroxy 3[3,17'fi-dihydroxy-l',3,5'(10')- estratrien-17-yl]-2-butenoic acidlactone and the corresponding 4,4-dihydroxy-3-[3-alkoxyor 3-cycloalkoxy-17'fi-hydroxy-1',3',5(10')-estratrien-17'yl] 2 butenoic acid lactones,such as, for example,

when oxidized with peracetic acid or m-chloroperbenzoic acid in thepresence of acetic acid.

Similarly oxidation of the 3-acyloxy-l7a-[3-furyl]-1,3,5,(l'O)-estratrien-17-ols described in U.S. Patent No. 3,271,392,yields 4,4-dihydroxy 3[3-acyloxy-17';8-hydr0Xy-l',3',5'(10')-cstratrien-l7yl]-2-buten0ic acidlactones, such as for example: 4,4-dihydroxy-3-[3-acetoxy-17'B-hydroxy-1',3',5(10)-estratrien-17'-yl] 2 butenoic acid lacetone,4,4-dihydroxy-3-[17fi-hydroxy-3'-propionyloxy-1',3,5'(10)-estratrien-17'-yl]-2-butenoicacid lactone, and 4,4-dihydroxy-3-[3'-butanoyloxy-17'B-hydroxy-1',3,5'(10')-estratrien-17'-yl]-2-butenoic acid lactone.

EXAMPLE 39 A solution of4,4-dihydroxy-3-[l7fl-hydroxy-3'-meth0xy-1',3',5'(10')-estratrien-17-yl]-2-butenoicacid lactone (6 g.), obtained in Example 36, or 37, pyridine ('60 ml.),and acetic anhydride (60 ml.), is kept overnight at room temperature.The reaction is worked up as in Example 27. The crude product ischromatographed on silica gel and the fractions eluted with mixtures ofbenzene and ethyl acetate are combined and crystallized from methylenechloride-hexane yielding 4-acetoxy-3-17fl-hydroxy-3'-methoxy-1',3',5(10')-estratrien-17-y1]-4-hydroxy-2-butenoic acid lactone, M.P. 198-201 C.

By a similar procedure acylation of 4,4-dihydroxy-3- 17'B-hydroxy-3-methoxy-1',3',5'( 10') -es-tratrien-17'-yl] 2-butenoic acid lactonewith other acylating agents such as,- for example, propionic or butyricanhydrides, yields the corresponding4-acyloxy-3-[17p3-hydroxy-3'-methoxy 1',3,5'( 10')-estratrien-17-yl]-4-hydroxy-2-butenoic acid lactones such as, for example,4-hydroxy-3-[l7'fi-hydroxy-3'-methoxy-1',3',5'(10) estratrien-l7yl]4-propionyloxy-Z-butenoic acid lactone and 4-butanoyloxy-3-l7fl-hydroxy-3'-methoxy-l ',6 ,5 10')-estratrien-17-yl]-4-hydroxy-2-butenoic acid lactone.

By a similar procedure acylation of the 4,4-dihydroxy- 3 [3' alkoxyor3'-cycloalkoxy-17'p-hydroxy-1',3',5' (10)estratrien-17-yl]-2-butenoicacid lactones and the 4,4 dihydroxy-3-[3-acyloxy-17p-hydroxy-1,3,5'(10)-estratrien-l7-yl]-2-butenoic acid lactones, obtained in Example 38,yields respectively the 4-acyloxy-derivatives, such as, for example, the4-acetoxy-, 4-propionyloxyor 4butanoyloxy-3-[3'-acyloxy-17'p-hydroxy-1',3',5'(10')- droxy1,3',5(10)-estratrien-17'-yl]-4-hydroxy-2butenoic acid lactones, and the4-acetoxy-, 4-propionyloxyor 4butanoyloxy-3-[3'-acyloxy-17;3-hydroxy-1,3,5(10')-estratrien-17'-yl]-4-hydroxy-2-butenoic acid lactones.

Similarly acylation of4,4-dihydroxy-3-[3'-17'B-dihydroxy-1',3',5'(10')estratrien-17'-yl]-2-butenoicacid lactone, obtained in Example 38, gives the corresponding 4- acyloxy3-[3-acyloxy-17'p-hydroxy-1',3',5'( 10)-estratrien-17-yl]-4-hydroxy-2-butenoic acid lactones such as, forexample, 4-acetoxy-3-[3-acetoxy-l7fi-hydroxy-1,3,5(10)-estratrien-17yl]-4-hydroxy-2-butenoic acid lactone, 4hydroxy-3-[17'B-hydroxy- -propionyloxy-1',3, 510')-estratrien-17'-y1]-4-propionyloxy-Z-butenoic acid lactone, and4-butanoyloxy-3-[3-butanoyloxy-17,8-hydroxy1',3,5'(10')-estratrien-l7-yl]-4-hydroxy-2-bute noic acid lactone.

EXAMPLE 40 A mixture of 17B-acetoxy-17-[3'-furyl]-3-methoxy-1,3,5(10)-estratriene (5 g.), described in U.S. Patent No. 3,271,392,chloroform (50 ml.), peracetic acid (20 ml. of a 40% solution) andsodium acetate (2 g.) is stirred for minutes. The reaction is worked upas in Example 37, yielding 4,4-dihydroxy-3-[17'5-acetoxy-3'-methoxy-l',3,5(10)-estratrien-17'-yl]-2-butenoic acid lactone, purified bycrystallization with methanol-ether, M.P. 214- 216 C.

Similarly oxidation of the other 17-acy1oxy derivatives of 17a[3'-furyl]-3-methoxy-1,3,5(l0)-estrat1ien-17-ol, described in U.S.Patent No. 3,271,392, yields the corresponding 4,4-dihydroxy-3-17fl-acyloxy-3'-methoxy-1',3', 5'(10')-estratrien-17'-yl]-2-butenoicacid lactones, such as, for example,4,4-dihydroxy-3-[3'-methoxy-l7B-propionyloxy-1,3,5(10')-estratrien-17y1]-2-butenoicacid lactone, and 4,4-dihydroxy-3-[l7fi-butanoy1oxy-3'-rnethoxy 1', 3',5(10) estratrien-17'-yl]-2-butenoic acid lactone.

EXAMPLE 41 A solution of 4,4-dihydroxy-[l7p-acetoxy-3'-methoxy-1',3,5'(10)-estratrien-17'-yl]-2-butenoic acid lactone (1.5 g.) obtainedin Example 40, pyridine (15 ml.), and acetic anhydride (15 m1.) is leftat room temperature for 16 hours. The reaction is worked up as inExample 27, and the residue is chromatographed on silica gel. Thefractions eluted with mixtures of ethyl acetate and benzene are combinedand crystallized from methylene chloride-hexane to yield4-acetoxy-3-[17fi-acetoxy-3'- methoxy1',3,5'10')-estratrien-17'-yl]-4-hydroxy-2-butenoic acid lactone, M.P.229-231 C.

EXAMPLE 42 A solution of 1718-[3'-furyl]-3-methoxy-1,3,5(I0)-estratriene(14.5 g.), obtained in Example 2, chloroform 19 (145 ml.), peraceticacid (14.5 ml. of a 40% solution), and sodium acetate (1.45 g.), isstirred for 30 minutes at room temperature. The reaction is worked up asin Example 37, yielding 4,4-dibydroxy-3-[3-methoxy-1,3,5(10')estratrien-17'5-y1]-2-butenoic acid lactone, purified bycrystallization with ether, M.P. 191-194 C.

By a similar procedure oxidation of 175-[3'-furyl]-1,3,5(10)-estratrien-3-o1, obtained in Example 2, yields 4,4 dihydroxy 3[3'-hydroxy-1,3,5'(10)estratrien- 175-yl] -2-butenoic acid lactone.

EXAMPLE 43 To a mixture of 175-[3'-furyl]-3-methoxy-1,3,5(10)-estratriene (6.84 g.), chloroform (342 ml.), sodium acetate (6.84 g.),and acetic acid (6.84 ml.) is added at room temperature to a solution of85% m-chloroperbenzoic acid (9.5 g.), in chloroform (95 ml.). Thereaction mixture is stirred at room temperature for 1 hour and thereaction product is isolated as in Example 36, yielding4,4-dihydroxy-3-[3-methoxy-1',3',5'(10)-estratrien- 17'5-yl]-2-butenoicacid lactone.

EXAMPLE 44 By a procedure similar to those described in Example 42 or 43the other 3-alkoxy-175-[3-furyl]-1,3,5(10)- estratrienes and the3-cycloalkoxy-175-[3-furyl]-1,3,5 (10)-estratrienes, obtained in Example2, are respectively transformed into the corresponding 4,4-dihydrxy-3-[3 alkoxyor 3-cycloa1koxy-1',3,5'(10')-estratrien- 17'5-yl1-2-butenoicacid lactones, such as for example:

4,4 dihydroxy-3-[3-ethoxy-1,3,5'( 10')-estrat.rien-17'5- yl] -2-butenoicacid lactone, 4,4-dihydroxy-3- 3'-propoxy-1',3,5 10' -estratrien-17'5-yl]-2-butenoic acid lactone, 4,4-dihydroxy-3-[3-isopropoxy-1',3,5 (10)-estratrien- 17'5-yl]-2-butenoic acid lactone,4,4-dihydroxy-3-[3-n-butoxy1',3',5'(10')-estratrien 17,-yl] -2-butenoicacid lactone, 4,4dihydroxy-3- [3 '-sec.-butoxy-1',3 ,5'(10')-estratrien-17'5-yl]-2-butenoic acid lactone,4,4-dihydroxy-3-[3'-cyclopentyloxy-1,3',5'(10')-estratrien-17'5-yl]-2-butenoic acid lactone, and 4,4-dihydroxy-3- [3'-cyclohexyloxy-1',3',5'(10')-estratrien-17'5-yl]-2-buten0ic acidlactone.

Similarly oxidation of the 3-acyloxy-175-[3-furyl]-1,3, 5()-estratrienes, obtained in Example 2, yields 4,4-dihydroxy 3[3'-acyloxy-1',3',5'(10')-estratrien-175-yl]- 2-butenoic acid lactones,such as, for example: 4,4-dihydroxy 3[3'-acetoxy-1',3',5'(10)-estratrien-17'5-yl] -2- butenoic acid lactone,4,4-dihydroxy-3-[3'-propionyloxy-1',3',5'(10')-estratrien-17'5-yl1-2-butenoic acid lactone, 4,4dihydroxy3-[3'-butanoyloxy-1',3,5'(l0')-estratrien- 17'5-yl1-2-butenoicacid lactone.

EXAMPLE 45 A solution of 4,4 dihydroxy 3-[3'-methoxy-1',3',5'(l0)-estratrien-17'5-yl]-2-butenoic acid lactone (7.05 g.), obtained inExample 42, or 43, pyridine (70 ml.), and acetic anhydride (70 ml.), isleft overnight at room temperature. The reaction is worked up as inExample 27 and the residue is crystallized from acetone-methanol to give4 acetoxy-3-[3'-methoxy-1,3',5'(10)-estratrien-17'5-yl]-4-hydroxy-2-butenoic acid lactone, M.P. 23 6238 C.

By a similar procedure acylation of 4,4-dihydroxy-3- [3' methoxy1',3,5'(l0')-estratrien-17'5-yl]-2-butenoic acid lactone with acylatingagents other than acetic anhydride, such as, for example, propionic orbutyric anhydrides, yield the corresponding 4-acyloxy-3-[3'-methoxy-1',3,5(10') estratrien 17'5 yl]-4-hydroxy-2-butenoic acid lactones, suchas, for example 4-hydroxy-3-[3-methoxy 1,3',5'(10')estratrien-l75-yl]-4-propionyloxy-2- butenoic acid lactone, and4-butanoyloxy-3-[3'-methoxy- 1',3 ',5 10')-estratrien-175-yl]-4-hydroxy-2-buten0ic acid acid lactone.

By a similar method acylation of 4,4-dihydroxy-3-[3'- 20 hydroxy1',3',5'(10') estratrien-17'5-yl]-2-butenoic acid lactone, obtained inExample 42, yields the corresponding 4 acyloxy3-[3-acyloxy-1',3',5'(10')-estratrien-17,5 yl]-4-hydroxy-2-butenoic acidlactones such as, for example: 4 acetoxy3-[3-acetoxy-1',3',5(l0')-estratrien- 17'5 yl] 4-hydroxy-2-butenoic acidlactone, 4-hydroxy- 3 [3 propionyloxy-1',3',5(10')-estratrien-175-yl]-4-propionyloxy-Z-butenoic acid lactone and 4-butanoyl0xy- 3 [3'butanoyloxy-1,3',5'(10)-estratrien-17'5-yl]-hydroxy-Z-butenoic acidlactone.

Similarly acylation of the 4,4-dihydroxy-3-[3-alkoxyor 3'cycloalkoxy-1,3',5(10')-estratrien-17'5-yl1-2-butenoic acid lactones andthe 44-dihydroxy-3-[3'-acyloxy- 1,3,5(10')-estratrien-175-yl]-2-butenoicacid lactones, obtained in Example 44, yields respectively the corresponding 4-acyloxy derivatives such as, for example the 4-acetoxy-,4-propionyloxy-, or 4butanoyloxy-3-[3-alkoxyor3'-cycloalkoxy-1,3',5(10')-estratrien-175-y1]-4- hydroxy-Z-butenoic acidlactones and the 4-acetoxy-, 4- propionyloxyor 4 butanoyloxy 3[3'-acyloxy-1,3,5' (10) estratrien 175 yl]-4-hydroxy-2-butenoic acidlactones.

EXAMPLE 46 A mixture of 17a [3'-furyl]-17-hydroxy-4-androsten- 3-one(2.5 g.), obtained in Example 3, chloroform (25 ml.), peracetic acid(2.5 ml. of a 40% soltuion), and sodium acetate (1 g.), is stirredovernight at room temperature. The reaction is worked up as in Example37 yielding 4,4 dihydroxy 3 [175-hydroxy-3-oxo-4'-androsten-17'-yl]-2-butenoic acid lactone.

Similarly oxidation of [3'-furyl]-l7-hydroxy-4- androstene-3,1l-dione,described in Example 6, l7u-[3'- furyl] 17 hydroxy-4-estren-3-one and17a-[3'-furyl]- 17-hydroxy-4-estrene-3,1l-dione, obtained in Example 5,and 115,175 dihydroxy-17-[3'-furyl]-4-androsten-3-one, and 115,175dihydroxy-17-[3'-furyl]-4-estren-3-one, prepared in Example 11,respectively yields,

4,4-dihydroxy-3-[3',11'-dioxo-l7'5-hydroxy-4-androstenl7'-yl]-2-butenoicacid lactone,

4,4-dihydroxy-3-[175-hydroxy-3'-oxo-4'-estren-17'-yl]- Z-butenoic acidlacetone,

4,4-dihydroxy-3-[115,17'5-dihydr0xy-3 '-oxo-4'-estren- 17'-y1]-2-butenoic acid lactone,

4,4-dihydroxy-3-[11'5-17'5-dihydroxy-3'-oxo-4'-androsten-17'-yl]-2-butenoicacid lactone, and

4,4-dihydroxy-3-[11'5,175-dihydroxy-3'-oxo-4-estren- 17'-yl]-2-butenoicacid lactone.

EXAMPLE 47 A solution of 4,4-dihydroxy-3-[17'5-hydroxy-3'-oxo-4'-androsten-17-yl]-2-butenoic acid lactone (1.98 g.), obtained in Example46, pyridine (20 ml.), and acetic anhydrides, yield the corresponding4-acyloxy-3-( [3'-meth0xyreaction is worked up as in Example 27, and theresidue is chromatographed on silica gel. The fractions eluted withmixtures of benzene and ethyl acetate are combined and crystallized fromacetone-hexane to give 4-actoxy-3-[175- hydroxy 3oxo-4'-androsten-17-yl]-4-hydroxy-2-butenoic acid lactone, M.P. 238-24C.

By a similar procedure acetylation of4,4-dihydroxy-3-[3',11-dioxo-175-hydroxy-4-androsten- 17-yl]-2-butenoicacid lactone,

4,4-dihydroxy-3-[ 17 '5-hydroxy-3 '-oxo-4-estren-17'-yl]- 2-butenoicacid lactone,

4,4-dihydroxy-3- [3 1 1-dioxo-175-hydroxy-4-estren- 17'-yl]-2-butenoicacid lactone,

4,4-dihydr0xy-2-[11'5,17'5-dihydroxy-3-oxo-4'-androsten-17-yl]-2-butenoic acid lactone, and

4,4-dihydroxy-3-[1 1'5, 17 '5-dihydroxy-3 '-oxo-4'-estren-17-yl]-2-butenoic acid lactone yields respectively:

4-acetoxy-3-[3',1 1-dioxo-17'5-hydroxy-4'-androsten-17-yll-4-hydroxy-2-butenoic acid lactone,

21 4-acetoxy-3-[17'fl-hydroxy-3 '-oxo-4'-estren-17'-yl]-4-hydroxy-2-butenoic acid lactone,4-acetoxy-3-[3,11-dioxo-17'B-hydroxy-4-estren-17'-yl]-4-hydroxy-2-butenoic acid lactone, 4-acetoxy-3-[ 1lfi,17'fl-dihydroxy-3'-oxo-4-androsten-17' yl]-4-hydroxy Z-butenoic acidlactone, and 4-acetoxy-3- l 1'13, 17 'fi-dihydroxy-3 '-oxo-4-estren-17'-yl]-4-hydroxy-2-butenoic acid lactone.

EXAMPLE 48 A mixture of 17 3-[3'-i5uryl]-4-androsten-3-one (2.3 g.),

obtained in Example 19, chloroform (23 m1.), peracetic acid (2.3 ml. ofa 40% solution), and sodium acetate (230 mg), is stirred at roomtemperature for 42 hours.

The crystalline insoluble product that forms is filtered and furthercrystallized from methanol yielding4,4-dihydroxy-3-[3'-oxo-4'-androsten-17'fl-yl] -2-butenoic acid lactone,M.P. 270-273" C.

In the same manner oxidation of 17;3-[3'-furyl]-4- estren-3-one,obtained in Example 19, 17 8-[3'-furyl]-4- androstene-3,11-dione, and17,3-[3-furyl]-4estrene-3,l1- dione, described in Example 20, yieldsrespectively 4,4- dihydroxy-3-[3'-oxo-4'-estren-17';3-yl] -2-butenoicacid lactone, 4,4-dihydroxy-3-[3',1 1'-dioxo-4'-androsten-l7fl-yl]Z-butenoic acid lactone, and4,4-dihydroxy-3-[3,l1'-dioxo-4'-estren-17-yl] -2-butenoic acid lactone.

EXAMPLE 49 EXAMPLE 50 A solution of4,4-dihydroxy-3-[3'-oxo-4'-androstenl7B-yl1-2-butenoic acid lactone (2.1g.), obtained in Example 48, pyridine (25 ml.), and acetic anhydride (25ml.), is left at room temperature for 16 hours. The reaction is workedup as in Example 27, and the residue is chromatographed on silica gel.The fractions eluted with mixtures of benzene and ethyl acetate arecombined and crystallized from acetone-hexane to yield 4-acetoxy-3-[3'-oxo-4'-androsten-17'B-yl]-4=hydroxy-2-b utenoic acid lactone, M.P.234-237 C.

Similarly acetylation of 4,4-dihydroxy-3-[3'-oxo-4-estren-17'B-yl]-2-butenoic acid lactone, 4,4-dihydroxy-3-[3,11'-dioxo-4'-androsten-17'5-yl] -2-butenoic acid lactone and4,4-dihydroxy-3-[3',l1"dioxo-4'-estren-17' 3-y1]- Z-butenoic acidlactone, described in Example 48, yields respectively4-acetoxy-3-[3'-oxo-4-estren-l7l8-yl]-4-hydroxy-2-butenoic acid lactone,4-acetoxy-3-[3',1l-dioxo- 4-androsten-17,B-yl]-4-hydroxy-2-lbutenoicacid lactone, and 4 acetoxy 3 [3,11' dioxo 4' estren -17,B yl]-4-hydroxy-2-butenoic acid lactone.

By a similar procedure, acetylation of 4,4-dihydroxy-3- [11;8 hydroxy 3'oxo 4 androsten 17'5 -yl] 2- butenoic acid lactone, and4,4-dihydroxy-3-[ 1 l'fi-hydroxy- 3'-oxo-4'-estren-17'B-yl] -2-butenoicacid lactone, yields respectively 4-acetoxy-3-[ 1 1,B-hydroxy-3'-oxo-4'-androsten-17'5-yl]-4-hydroxy-2-butenoic acid lactone, and 4-acetoxy 3 [ll'fi hydroxy 3 oxo 4' estren 17'5- yIJ-hydroxy-Z-butenoicacid lactone.

EXAMPLE 51 A mixture of 17a-[3'-furyl]-17-hydroxy-Sa-androstan- 3-one(5.0 g.), obtained in Example 23, chloroform (50 ml.), peracetic acid(40 ml. of a 40% solution), sodium acetate (4.0 g.), is stirred at roomtemperature for 15 minutes. The reaction is worked up as in Example 37to yield 4,4-dihydroxy-3-[l7' 3-hydroxy-3'-oxo5a-androstanl7'-yl]-2-butenoic acid lactone, purified by crystallizationwith methylene chloride-hexane, M.P. 260-262 C.

Similarly oxidation of 17a-[3'-furyl]-l7-hydroxy-5fiandrostan 3 one, [3'furyl] 17 hydroxy 5aandrostane-3,11-dione, and 17u-[3-furyl]-l7-hydroxy-5 3-androstane-3,l1-dione, obtained in Example 23, yields respectively4,4-dihydroxy-3-[17p-hydroxy-3'-oxo-5,8-androstan-17-yl]-2-butenoic acidlactone, 4,4-dihydroxy-3- [3,11 dioxo 175 hydroxy 5'a androstan 17'-yl]-2-butenoic acid lactone, and 4,4-dihydroxy-3-[3',11'-dioxo-17B-hydroxy-5p-androstan-17'-yl]-2-butenoic acid lactone.

By a similar procedure, oxidation of 11fl,l7p-dihydroxy- 17 [3' furyl]5a androstan 3 one, and1lfi,l7fldihydroxy-l7-[3'-fiuryl]-5fl-androstan-3-one yieldsrespectively 4,4-dihydroxy-3-[ l1'3,17fl-dihydroxy-3'-oxo-5'aandrostan-17'-y1]-2-butenoic acid lactoneand 4,4-dihydroxy 3 [11'p,17',3 dihydroxy 3' oxo *S'flandrostan-l7-yl]-2-butenoic acid lactone.

EXAMPLE 52 A mixture of 3/3-acetoxy-17w[3-furyl]-5u-androstan- 17-01(1.2 g.), obtained in Example 27, chloroform (50 ml.), peracetic acid(1.2 ml. of a 40% solution) and sodium acetate (1.2 g.), is stirred atroom temperature for 1 hour. The reaction is worked up as in Example 37,and the residue is crystallized from ether to give 4,4-dihydroxy 3 [3'5acetoxy 1716 hydroxy S'aandrostan-17'-yl]-2-butenoic acid lactone, M.P.2518-26-2" C.

Similarly oxidation of 17a-[3-furyl]-3B-propionyloxy- 5a-andro'stan-17-0l, and 3fiw'b'utanoyloxy-17u-[3'-fury1]-5aandrostan-17-ol yields respectively 4,4-dihydroxy-3-[17fihydroxy 3'5propionyloxy 5a androstan 17' yl]- Z-butenoic acid lactone and4,4-dihydroxy-3-[3p-butanoyloxy 17' hydroxy Sa androstan 17' yl] 2-butenoic acid lactone.

By a similar manner oxidation of the 3fi-acyloxy-l7a-[3'-furyl]-5B-anclrostan-17-ols, obtained in Example 27, yields thecorresponding 4,4-dihydroxy-3-[3'fi-acyloxy-17'fi-hydroxy-S'fl-androstan-17'-yl]-2-butenoic acid lactones.

In a similar manner oxidation of17u-[3'-furyl]-'5a-androstane-3fl,17-diol and17a-[3'-furyl]-5p-androstane-3,8, 17-diol, described in Example 26,yields respectively, 4,4 dihydroxy 3 [3'fi,17'}8 dihydroxy 5'0:androstan-17'-yl]-2-butenoic acid lactone, and 4,4-dihydroxy- 3 [318,175dihydroxy 5'5 androstan 17'yl] 2- butenoic acid lactone.

EXAMPLE 53 Acetylation as described in Example 39, of 4,4-dihydroxy 3[3',B,l7'/3 dihydroxy 5'u androstan-17'- yl]-2-butenoic acid lactone,and 4,4 dihydroxy 3-[3;8, 175 dihydroxy-S'fl-androstan-17-yl] 2 butenoicacid lactone, obtained in Example 52, yields respectively, 4 acetoxy 3[3;3-acetoxy-17'fi hydroxy 5'u-androstan-17-yl] 4 hydroxy 2 butenoicacid lactone, and 4-acetoxy 3 [S'fi-acetoxy 17',Bhydroxy-S'fl-androstan-17'yl]-4-hydroxy-2-butenoic acid lactone.

By a similar manner acetylation of the 4,4-dihydroxy- 3 [3;8 -acyloxy17'fi hydroxy 5'0: androstan-l7- yl]-2 butenoic acid lactones, and 4,4dihydroxy-3-[3'fl, acyloxy-17',8-hydroxy-5'B-androstan-l7-yl] 2 butenoicacid lactones, obtained in Example 52 yields respectively the4-acetoxy-3-[3'fi-acyloxy-l7'B-hydroxy-Soz-androstan-17'-yl]-4-hydroxy-2-butenoic acid lactones and the 4-acetoxy 3[3,8-acyloxy-17'p-hydroxy 5'13 androstan- 17'-yl]-4-hydroxy-2-butenoicacid lactones.

Similarly,

23 4,4-dihydroxy-3 17fl-hydroxy-3 '-oxo-5 a-androstan-17'-yl]-2-butenoic acid lactone, 4,4-dihydroxy-3-[17B-hydroxy-3 'oxo-S'18-androstan- 17'-yl]-2-butenoic acid lactone,4,4-dihydroxy-3-[3,1l'-dioxo-17'B-hydroxy-5'uandrostan17'-yl]-2-butenoicacid lactone, 4,4-dihydroxy-3-[3,1 1'-dioxo-17'fi-hydroxy-5 '5-androstan-17'-yl] -2-butenoic acid lactone, 4,4-dihydroxy-3-[1 1'5, 17'p-dihydroxy-3 '-oxo-5 '0:- androstan-17-yl]-2-butenoic acid lactone,and 4,4-dihydroxy-3[ l 1'fl,17';8-dihydroxy-3 '-oxo-5 '5-androstan-17-yl]-2-buten0ic acid lactone,

described in Example 51, are acetylatcd to yield respectively4-acetoxy-3-[ l7fl-hydroxy-3-oxo-5 a-androstan- 17'-yl4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3- 17'fl-hydroxy-3 -oxo-5B-androstanl7-yl]4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3- [3 '11-dioxo-17'B-hydroxy-S'a-androstan-17'-yl]-4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3- 3 ,1 1'-dioxo-17;3-hydroxy-5 'fl-androstan-17-yl]-4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3-[1 1'13,1718-dihydroxy-3-oxo-5a-androstan-17'-yl]-4-hydroxy-2-bntenoic acid lactone, and

4-acetoxy-3-[11fi-dihydroxy-3 -oxo-5 'fl-androstan-17'-yl]-4-hydroxy-2-butenoic acid lactone.

EXAMPLE 54 A mixture of 17fi-[3'-furyl]-5a-androstan-3-one 3.8 g.),obtained in Example 30, chloroform (100 ml.), peracetic acid (3.8 ml. ofa 40% solution), and sodium acetate (3.8 g.) is stirred at roomtemperature for 1 hour. The reaction is worked up as in Example 37, togive 4,4 dihydroxy 3-[3' x0 S'm androstan 17'fl-yl]-2- butenoic acidlactone, purified by crystallization with ether, M.P. 284289 C.

Similarly oxidation of 17B-[3'-furyl]-5fi-androstan-3- one,17;3-[3'-furyl]-5a-androstane 3,11 dione, and 17B-[3-furyl]-5fl-androstane-3,1l-dione, obtained in Example 30, yieldsrespectively 4,4-dihydroxy-3[3'-oxo-5'fi-androstan-17fi-yl]-2-butenoicacid lactone, 4,4-dihydroxy-3-[3',11-dioxo-5'a-androstan-17fi-yl]-2-butenoic acid lactone, and 4,4dihydroxy-3-[3',11'-dioxo-5'fl-androstan 17'5- yl]-2-butenoic acidlactone.

EXAMPLE 5 A mixture of 3B- acetoxy-17fi-[3furyl1-5a-androstane (150mg.), obtained in Example 30, chloroform (7.5 ml.), peracetic acid (0.6ml. of a 40% solution), and sodium acetate (60 mg.) is stirred at roomtemperature as in Example 37. The crude reaction product is crystallizedfrom methylene chloride-ether to give4,4-dihydroxy-3-[3'fi-acetoxy-S'a-androstan-17'fl-yl] Z-butenoic acidlactone, M.P. 254-256 C.

By a similar procedure, but replacing chloroform by acetone, benzene,dioxan, methanol, tetrahydrofuran, ethyl acetate, ether, or acetic acid,3fi-acetoxy-17'13-[3- furyH-Su-andmstane is oxidized with peracetic acidfor periods of time ranging from 1 hour to 60 hours to give4,4-dihydroxy-3-[3B-acetoxy-5'a androstan 1738 yl]- 2-butenoic acidlactone, identical in all respects with the product obtained whenchloroform is the solvent.

Similarly the other BB-acyloxy-17fl-[3'-furyl]-5u-androstanes, describedin Example 30 are oxidized to the corresponding 4,4dihydroxy-3-[3'fl-acyloxy-S'a-androstan- 17fi-yl]-2-butenoic acidlactones such as, for example 4,4-dihydroxy-3-[3fi-propionyloxy S'aandrostan-17fiyl] 2 butenoic acid lactone and4,4-dihydroxy-3-[3flbutanoyloxy-S'a-androstan 175 yl] 2 butenoic acidlactone.

By a similar procedure oxidation of 17,3-[3-furyl]-5aandr0stan-3/3-ol,17p-[3'-furyl]-5p-androstan-318-01, and the 3fl-acyloxy-173-[3-fury1]-5,8-andr0stanes, obtained in Example 30 yields respectively4,4-dihydroxy-3-[3B-hy- 24 droxy-S'a-androstan-lTB-yl]-2-butenoic acidlactone, 4,4- dihydroxy 3 [3;8-hydroxy 5 '13 androstan-1713-yl]-2-butenoic acid lactone and 4,4-dihydroxy-3-[3B-acyloxy-5fl-androstan-l7fl-yl]-2-butenoic acid lactones.

EXAMPLE 5 6 Acetylation as in Example 39 of4,4-dihydroxy-3-[3fihydroxy-5'a-andr0stan-17fl-yl]-2-butenoic acidlactone, and 4,4-dihydroxy-3-[3'fi-hydroxy-S'fi-androstan-l7fl-yl]-2-butenoic acid lactone, yields respectively 4-acetoxy-3-[3'B-acetoxy-S'u-androstan-17p-yl]-4-hydroxy-2-butenoic acid lactone and4acetoxy-3-[3' 3-acetoxy-S'fl-androstanl7fl-yl]-4-hydroxy-2-butenoicacid lactone.

Similarly acetylation of the 4,4-dihydroxy-3-[3'fl-acyl-0xy-5'a-andr0stan-17fl-ylJ-2-butenoic acid lactones, and the4,4-dihydroxy-3- [3 'fi-acyloxy-S'fl-androstan-17'fi-yl]- Z-butenoicacid lactones, yields the corresponding 4-acetoxy-3-[313-acyloxy 5'aandrostan-17'f3-yl]-4-hydroxy- Z-butenoic acid lactones and4-acetoxy-3-[3'fi-acyloxy- Sfl-androstan-17'13-yl]-4-hydroxy-2-butenoicacid lactones.

By a similar procedure, acetylation of4,4-dihydroxy-3-[3-oxo-5'm-androstan-17',8-yl]-2- butenoic acid lactone,

4,4-dihydroxy-3-[3'-oxo-5 S-androstan-17'13-y11-2- butenoic acidlactone,

4,4-dihydroxy-3- [3 ',1 1-dioxo-5 'a-androstan-17'p-yl] -2- butenoicacid lactone, and

4,4-dihydroxy-3- [3 ,11-dioxo-513-andr0stan-17fl-yl]-2- butenoic acidlactone,

yields respectively:

4-acetoxy-3-[3-oxo-5a-androstan-17'13-yl]-4-hydroxy-2- butenoic acidlactone,

4-acetoxy-3 [3 '-oxo-5 'B-androstan- 17'fi-y11-4-hydroxy-2- butenoicacid lactone,

4-acetoxy-3- 3',1 1-dioxo-5'a-androstan-17'fl-yl] -4- hydroxy-Z-butenoicacid lactone, and

4-acetoxy-3-[3', 1 1'-diox0-5fi-androstan-17fi-yl]-4- hydroxy-Z-butenoicacid lactone.

EXAMPLE 57 By a similar procedure as described in Example 36 or 37,

are transformed respectively by oxidation to:

4,4-dihydroxy-3-[17'f3-acetoxy-3 -oxo-4-androsten-1 7- yl]-2-butenoicacid lactone,

4,4-dihydroxy-3-[17fl-acetoxy-3 '-oxo-4'-estren-17-yl]-2- butenoic acidlactone,

4,4-dihydroxy-3-[17'fl-acetoxy-3 ,11'-dione-4'-estren-17'-yl]-2-butenoic acid lactone,

4,4-dihydroxy-3-[ l7B-acetoxy-3'-oxo-5'a-androstan-17- yIJ-Z-butenoicacid lactone,

4,4-dihydroxy-3-[1713-acetoxy-3 ',11'-dioxo-5'u-androstan-17-yl]-2-butenoic acid lactone, and

4,4-dihydroxy-3 -[17,B-acet0xy-3 ',11'-dioxo-5'fi-androstan-17-yl]-2-butenoic acid lactone.

25 EXAMPLE s Acetylation as in Example 39 of 4,4-dihydroxy-3-17'5-acetoxy-3 '-oxo-4'-androstenl7- yl]-2-butenoic acid lactone,

4,4-dihydroxy-3- 17 '5-acetoxy-3 '-oxo-4'-estren-17-yl] -2- butenoicacid lactone,

4,4-dihydroxy-3- 17'5-acetoxy-3', 1 l'-dioxo-4'-estren-17'-yl]-2-butenoic acid lactone,

4,4-dihydroxy-3-[ 17'5-acetoxy-3',1 1',-dioxo-4'-androsten-17-yl]-2-butenoic acid lactone,

4,4-dihydroxy-3-[ 175-acetoxy-3'-oxo-5'a-andr0stan-17'- yl]-2-butenoicacid lactone,

4,4-dihydroxy-3-[17'5-acetoxy-3'-oxo-55-androstan-17'- yl]-2-butenoicacid lactone,

4,4-dihydroxy-3- l7'5-acetoxy-3 1 1'-dioxo-Sa-androstanl7'-yl]-2-butenoic acid lactone, and

4,4-dihydroxy-3-[ l7'5-acetoxy-3 l 1-dioxo-5 '5-androstan-17'-yl]-2-butenoic acid lactone yields respectively:

4-acetoxy-3-[17'5-acetoxy-3 '-oxo-4'-androsten-17-yl]-4-hydroxy-Z-butenoic acid lactone,

4-acetoxy-3-[ 175-acetoxy-3 '-oxo-4'-estranl7'yl] -4- hydroxy-2-butenoicacid lactone,

4-acetoxy-3-[17'5-acetoxy-3 ',11-dioxo-4'-estren-17'-yl]-4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3-[175-acetoxy-3 ',11'-dioxo-4-androsten-l7-yl]-4-hydroxy-2-butenoic acid lactone,

4acetoxy-3- 1 7'5-acetoxy- -oxo-5'a-androstan-17'-yl]4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3-[ 17'5-acetoxy-3 '-oxo-5'5-androstan-17-yl]-4-hydroxy-2-butenoic acid lactone,

4-acetoxy-3-[17'5-acetoxy-3',l 1'-dioxo-5'a-androstan-17-yl]-4-hydroxy-2-butenoic acid lactone, and

4-acetoxy-3-[ 17'5-acetoxy-3',11-dioxo-5'5-androstan-l7-yl]-4-hydroxy-2-butenoic acid lactone.

EXAMPLE 59 A mixture of 35-acetoxy-175-[3'-furyl]-55-androstan- 145-01,obtained in Example 34 (1 g.), anhydrous sodium acetate (1 g.), 40%peracetic acid (1 ml.), and chloroform (25 ml.), is stirred at roomtemperature for 30 minutes. The reaction mixture is diluted withchloroform and the organic layer is washed with water until free ofperacid. The chloroform is dried and evaporated to dryness. The residueis triturated with acetone (15 ml.), and the resulting solid iscrystallized from aqueous tetrahydrofuran thus yielding35-acetoxy-14,21-dihydroxy-55- card-20(22)-enolide, M.P. 192-196 C.

Similarly, 35-acetoxy- 175- [3'-furyl] -androstane-55, 145- diol,35-acetoxy-55,145-dihydroxy-175-[3'-furyl]-androstan-19-al and35,l9-diacetoxy-l75-[3-furyl]-androstane- 55,145-dio1 obtained inExample 34, yield when treated as above, with peracetic acid35-acetoxy-55,14,2l-trihydroxycard-20(22)-en0lide,35-acetoxy-l9-oxo-55,14,21- trihydroxycard 20(22) enolide and 35,19diacetoxy- 55,14,2l-trihydroxycard-20(22)-enolide.

In a similar manner oxidation with peracetic acid of the 3-propionatesor 3-butyrates of l75-[3'-furyl]-55- androstane 35,145 diol, 175 [3'furyl] androstane- 35,55,145-triol and175-[3'-furyl]-35,55,l45-trihydroxyandrostan-19-al described in Example35, yield the corresponding 3-propionates or 3-butyrates of35,14,21-trihydroxy 55 card-20(22)-enolide, 35,55,l4,2l-tetrahydroxycard-20(22)-enolide andl9-0xo-35,55,14,2l-tetrahydroxycard-20(22)-enolide, respectively.

In the same manner the 35,1-9-dipropionate, and 35,19- dib utyrate of175 [3-furyl]-androstane-35,55,145,19- tetrol, obtained in Example 35,yield the corresponding 35,19-dipropionate, and 35,19-dibutyrate of35,55,14,l9,- 2 l-pentahydroxycard-20( 22) -enolide, respectively.

EXAMPLE 60 By the same procedure as described in Example 59, 175- [3'furyl]-55-androstane-35,145-dio1, -[3-furyl]-androstane-35,55,145-triol,175-[3'-furyl]-androstane-35,55,- 145,19-tetrol obtained in Example 32,and 175-[3-furyl]- 35,55,145-trihydroxyandrostan-19-al, obtained inExample 33 are treated with peracetic acid to yield, respectively,35,14,21-trihydroxy-55-card-20(22)-eno1ide, 3 5,5 5, 14,21-tetrahydroxycard-20( 22) -enolide,35,55,14,19,21-pentahyd-roxycard-20(22)-enolide, and19-oxo-35,55,14,21-tetrahydroxycard-20(22)-enolide.

EXAMPLE 61 A solution of 35 acetoxy-l4,2l-dihydroxy-55-card-20(22)-enolide (500 mg.), described in Example 59, pyridine (10 ml), andacetic anhydride (5 ml.), is allowed to stand at room temperatureovernight. Methanol (5 ml.) is added, and the solution is poured intoice-water and extracted with ether. The ether is washed with dilutesulfuric acid, sodium bicarbonate and water, dried and evaporated todryness. The residue is crystallized from ether to yield35,21-diacetoxy-14-hydroxy-55-card-20(22)- enolide, M.P. 19l C.Similarly, acetylation of 35- acetoxy55,l4,21-trihydroxycard-20(22)-enolide, 35-acetoxy-l9-oxo-55,14,21-trihydroxycard-20(22)-enolide, and 35,19-diacetoxy-55,14,21-,trihydroxycard-20(22)-enolide, described in Example 59, yields35,2l-diacetoxy-55;14-dihydroxycard 20 (22)-enolide,35,21-diacetoxy-55,14-dihydroxy-19-oxo-card-20(22)-enolide, and55,14-dihydroxy- 3 5, 19,2 1-triacetoxycard-20( 22 -enolide,respectively.

In a similar manner, acetylation of the 3-propionates and 3 butyrates of35,14,21 trihydroxy 55 card 20(22)- enolide,35,55,14,21-tetrahydroxycard-2O (22)-enolide, and 19oxo-35,55,14,21-tetrahydroxycard-20(22)-enolide described in Example 59,yields the coresponding 2l-acetates of the 3-propionates and 3-butyratesof 35,14,2l-trihydroxy 55 card 20(22) enolide,35,55,14,2l-tetrahydroxycard-20(22)-enolide, and19-oxo-35,55,14,21-tetrahydroxycard-20(22)-enolide, respectively.

By a similar procedure, acylation with the appropiate lower aliphaticacid anhydrides or acyl chlorides such as, for example, propionicanhydride or butyryl chloride, in pyridine, of the 3-acylatedderivatives of 35,14,21-trihydroxy 55 card 20(22) enolide,35,55,14,21-tetrahy droxycard 20 (22) enolide and19-oxo-35,55,14,21-tetrahydroxycard-20(22)-enolide and the35,19-diacylates of 35,55,14,19,21 pentahydroxycard 20(22) enolideobtained as described in Example 59, yields the corresponding mixed35,2l-diacylates and the corresponding mixed 35,19,21-triacylates, suchas, for example, the 35-acetate- 2-l-propionate or the35-acetate-21-butyrate of 35,14,21- trihydroxy 55 card 20(22)-enolide,35,55,14,21-tetrahydroxycard-20(22)-enolide, or l9-oxo-35,55,14,21-tetrahydroxycard 20(22) enolide; or the35,19-diacetate-2lpropionate or 35,19-diacetate-21-butyrate of35,55,14,19,- 2 l-pentahydroxycard-20(22) -en0lide.

EXAMPLE 62 Acylation with acetic anhydride, propionic anhydride, orbutyryl chloride by the procedure of Example 61, of 35,14,21 trihydroxy55 card-20(22)-enolide, 35,55,14,- 21 tetrahydroxycard-20(22)-enolide,and l9-oxo-35,55,- 14,21 tetrahydroxycard-20(22)-enolide obtained inExample 60 yields the corresponding 35,21-diacetates, 35,21-dipropionates, and 35,21 dibutyrates of35,14,21-trihydroxy-55-card-20(22)-enolide, 35,55,14,21-tetrahydroxycard20(22) enolide, and l9-oxo-35,55,14,21-tetrahydroxycard-20(22)-enolide,respectively.

Similarly, acylation as above, of35,55,14,19,21-pentahydroxycard-20(22)-enolide described in Example 60,yields the corresponding 35,19,21-triacetate, 35,19,21-tripropionate,and 35,19,21 tributyrate of 35,55,14,19,21-pentahydroxycard-20(22)-enolide, respectively.

wherein St is a steroid radical selected from those of the formulaejoined to the lactone ring at the 17-position of said steroid radical,and R is selected from the group which consists of hydrogen and loweraliphatic acyl; X represents hydrogen, hydroxyl, or lower aliphaticacyloxy; R represents hydrogen, a lower alkyl group containing from oneto four carbon atoms, a cycloalkyl group containing from five to sixcarbon atoms or acyl; R represents two atoms of hydrogen, a hydroxylgroup and a hydrogen atom, or an oxygen atom; R represents hydrogen ormethyl; and R represents hydroxyl, a lower aliphatic acyloxy group and ahydrogen atom, or an oxygen atom, the dotted lines in ring B of saidformula containing said dotted lines as appearing above indicating thattwo double bonds in positions 6,7 and 8,9 may be present.

2. 4,4 dihydroxy 3 [17'18 hydroxy 3' methoxy-1',3',5'(10')-estratrien-17'-yl]-2-butenoic acid lactone, as claimed inclaim 1.

3. 4,4 dihydroxy 3 [3' methoxy l',3,5'(10)-estratrien-lTfi-yl]-2-butenoic acid lactone, as claimed in claim 1.

4. 4,4 dihydroxy 3 [17'5 hydroxy 3 oxo 4'- androsten-l7'-yl]-2-butenoicacid lactone, as claimed in claim 1.

5. 4,4 dihydroxy 3 [3,11 dioxo 1713 hydroxy-4-androsten-l7-yl]-2-butenoic acid lactone, as claimed in claim 1.

6. 4,4 dihydroxy 3 [1173,1713 dihydroxy 3' oxo-4'-androsten-17-yl]-2-butenoic acid lactone, as claimed in claim 1.

7. 4,4 dihydroxy 3 [17;8 hydroxy 3 oxo 4'- estren-l7-yl]-2-butenoic acidlactone, as claimed in claim 1.

8. 4,4 dihydroxy 3 [3,11 dioxo 1716 hydroxy- 4'-estren-17-yl]-2-butenoicacid lactone, as claimed in claim 1.

9. 4,4 dihydroxy 3 [1l',8,17;8 dihydroxy 3'-oxo-4'-estren-17-yl]-2-butenoic acid lactone, as claimed in claim 1.

10. 4,4 dihydroxy 3 [3' oxo 4 androsten 17'5- yl]-2-butenoic acidlactone, as claimed in claim 1.

11. 4,4 dihydroxy 3 [3,1 1' dioxo 4' androstenl7'/3-yl]-2-butenoic acidlactone, as claimed in claim 1.

12. 4,4 dihydroxy 3 [11B-hydroxy 3 oxo 4'-androsten-17'fi-y1]-2-butenoic acid lactone, as claimed in claim 1.

13. 4,4 dihydroxy 3 [3 0x0 4' estren 17'5- yl]-2-butenoic acid lactone,as claimed in claim 1.

14. 4,4 dihydroxy 3 [3,11 dioxo 4' estren- 17fi-yl]-2-butenoic acidlactone, as claimed in claim 1.

15. 4,4 dihydroxy 3 [17'18 hydroxy 3 oxo 5'5-androstan-l7'-y1]-2-butenoic acid lactone, as claimed in claim 1.

16. 4,4 dihydroxy 3 [3,11' dioxo 1718 hydroxy-S'fi-androstan-17'-yl]-2-buten0ic acid lactone, as claimed in claim 1.

17. 4,4 dihydroxy 3 [l1';8,17}3 dihydroxy 3'-oxo-Sfl-androstan-17'-yl]-2-butenoic acid lactone, as claimed in claim1.

18. 3,8,14,21-trihydroxy-5/3-card-20(22)-enolide.

19. 35,5 3,14,2l-tetrahydroxycard-20(22)-enolide.

20. 3 5,513, 14, 19,2 l-pentahydroxycard-ZO (22 -enolide.

21. 19 oxo 3,8,55,14,21 tetrahydroxycard- 20(22)- enolide.

22. 35 acetoxy 14,21 dihydroxy 5,8 card 20(22)- enolide.

23. 3B acetoxy 5fi,14,2l trihydroxycard 20(22)- enolide.

24. 3B acetoxy 19 oxo 5,8,14,21 trihydroxycard- 20(22)-enolide.

25. The process which comprises subjecting a l7-[3'- furyl]-substitutedsteroid of the formula in which St represents a steroid radical selectedfrom the group which consists of wherein X represents hydrogen, hydroxylor lower ali- .phatic acyloxy; R represents hydrogen, a lower alkylgroup containing from one to four carbon atoms, a cycloalkyl groupcontaining from five to six carbon atoms or acyl; R represents two atomsof hydrogen, a hydroxyl group and a hydrogen atom, or an oxygen atom; Rrepresents hydrogen or methyl; R represents hydroxy or a lower aliphaticacyloxy group and a hydrogen atom, or an oxygen atom; R represents twoatoms of hydrogen, hydroxyl, a lower aliphatic acyloxy group and oneatom of hydrogen, or an oxygen atom; R represents hydrogen or a loweraliphatic acyl group; and Y represents hydrogen or hydroxyl, the dottedlines in ring B of said formula 29 30 containing said dotted lines asappearing above indicating References Cited that two double bonds inpositions 6,7 and 8,9 may be UNITED STATES PATENTS I present, to theaction of an organic peracid selected from the group which consists ofperacetic, perbenzoic, mono- 2,951,076 8/1960 PaPPo .260 239'57perphthalic, m-chloroperbenzoic acid and p-nitroper- OTHER REFERENCESbenzoic acid in the presence of a nucleophilic reagent se- 5 lected fromthe group which consists of acetic acid and Satoh {at Annalen def Chemle246453 p. 248 rehed on (June 1965).

water, thereby securing a compound of the formula Catala et a1: C'AI,v01. 61, CO1. 1732a (1964).

L I 10 HENRY A. FRENCH, Primary Examiner. HO O 0 US. 01. X.R.

wherein St is as above defined. 260239.5, 239.55, 397.4, 397.45; 424-241UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,436,390 April 1 1969 Yvon Lefebvre et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 5, formula XI should appear as shown below:

Signed and sealed this 7th day of April 1970.

(SEAL) Attest EDWARD M,FLETCHER,JR. WILLIAM E SCHUYLER, JR.

Attesting Officer Commissioner of Patents

